Bio-based green solvent mediated disulfide synthesis via thiol couplings free of catalyst and additive

Article abstract of DOI:10.1039/c3ra42915f

The bio-based green solvent ethyl lactate has been found to be a particularly efficient medium for oxidative coupling reactions of thiols yielding a broad array of disulfides. As a green solvent, ethyl lactate has shown an interesting promotion effect on the transformation by mediating corresponding reactions with high efficiency without using any catalyst or additive. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra42915f

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Bio-based green solvent mediated disulfide synthesis
via thiol couplings free of catalyst and additive†
Cite this: RSC Adv., 2013, 3, 21369
b
b
ab
Yunyun Liu,ab Hang Wang, Chunping Wang, Jie-Ping Wan
and Chengping Wen
*
c
*
Received 12th June 2013
Accepted 17th September 2013
DOI: 10.1039/c3ra42915f
www.rsc.org/advances
The bio-based green solvent ethyl lactate has been found to be a well as Hantzsch multicomponent reaction.5 However, exam-
particularly efficient medium for oxidative coupling reactions of ples of EL mediated reactions are still rare and much more
thiols yielding a broad array of disulfides. As a green solvent, ethyl efforts are desirable in order to explore more general applica-
lactate has shown an interesting promotion effect on the trans- tion of EL as green medium of organic reactions. Disuldes are
formation by mediating corresponding reactions with high efficiency important biologically relevant compounds possessing versatile
without using any catalyst or additive.
activities,6–8 moreover, they are also important industrial
materials in vulcanization process of rubbers and elastomers.
More importantly, as thiol sources, disuldes have been
extensively employed in the synthesis of sulfur containing
products in a variety of different synthetic routes.9–14 When
being used as reactants, the evident advantages of disuldes
over corresponding thiols are that disuldes usually show better
stability and are not foul-smelling as thiols. It is therefore
reasonable that the synthesis of disuldes has attracted
considerable interests during the past several decades. At
present, the most straightforward approach for disuldes
synthesis is the dehydrogenative coupling of thiols. A large
number of different catalytic protocols have been developed for
performing this transformation with elegant efficiency. Metal
reagents such as rhenium salt,15 copper salt,16 diamond sup-
ported copper nanoparticles,17 nickel,18 ferric chloride,19 chro-
mate,20 permanganate;21 nonmetal reagents such as sodium
chlorite,22 silica gel supported bromine,23 sodium nitrite,24
hydrogen peroxide,25 diaryl tellurides,26 montmorillonite K10,27
Et3N,28 N-phenyltriazolinedione,29 selenium-based ionic
liquid,30 graphite oxide,31 etc. have all been discovered to effec-
tively promote the coupling of thiols by serving as either oxidant
or catalyst of aerobic oxidation. In addition, mixed catalysts
such as FeCl3–NaI/air,32 cobalt–iron magnetic composites33 and
cobalt(II) phthalocyanines,34 nitro urea/silica sulfuric acid35 and
recyclable catalyst such as poly(4-vinylpyridinium nitrate)36 have
also been reported as efficient species for disuldes synthesis
using thiols. In most of these known approaches, either an
oxidant or a catalyst that promoted aerobic oxidation process
was employed, in some other cases, basic or acidic additives
have been utilized for initiating reactions. In different routes,
coupling reactions between aryl iodide and elemental sulfur has
been recently reported as efficient route for disulde synthesis
As sustainability has now evolved into a core issue of modern
chemical industry, developing reactions with reduced environ-
mental impact has become one of the principal challenges for
the chemical community. During the past decades, tremendous
efforts have been made to discover atom economical and envi-
ronmentally benign synthetic methodologies to replace tradi-
tional synthetic routes that bring environmental pressure.
Among the research contents of green chemistry, employing
nontoxic and low cost solvents as alternative reaction media
constitutes a major point and attracts worldwide attention.
Ethyl lactate (EL) is a typical completely biodegradable organic
solvent that could be easily obtained from biomass at low cost.
As nontoxic chemical, EL has been used broadly as food addi-
tives.1,2 Therefore, EL is an ideal green solvent since it produces
no environmental impact during utilization. Using bio-based
green solvent of this type caters to the principles of green
chemistry. In known efforts of exploring the function of EL as
medium of organic reactions, EL has been hitherto successfully
used for several different types of organic reactions, including
Suzuki–Miyaura reaction,3 amine–aldehyde condensation4 as
aKey Laboratory of Functional Small Organic Molecules, Ministry of Education, Jiangxi
Normal University, Nanchang 330022, P R China
bCollege of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang 330022,
P R China. E-mail: wanjieping@gmail.com; Fax: +86 791
88120380; Tel: +86 791 88120380
cCollege of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou
310053, P R China. E-mail: cpwen.zcmu@yahoo.com; Fax: +86 571 86633131; Tel:
+86 571 86633131
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra42915f
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Table 1 Optimization on reaction conditionsa
in the presence of copper catalyst.37 Rather recently, interesting
new methods have been developed for the synthesis disulde
via thiol coupling, Beifuss and co-workers discovered highly
efficient laccase-catalyzed thiol couplings, and the method is
particularly applicable for the synthesis of heteroaryl disul-
des,38a while Ranu et al. reported the solvent- and catalyst-free
ball milling approach for thiol coupling employing Al2O3 as
milling auxiliary.38b In despite of individual advantages of these
synthetic methods, the use of catalyst, additive or volatile
organic media are still problems needing improvement in order
to achieve cleaner synthesis of disuldes. In this regard,
developing reactions free of waste formation is highly desirable.
Based on our research interests in organic synthesis mediated
by green bio-based solvents, we wish to report herein the rst
approach for dehydrogenative coupling of thiols to suldes
using bio-based green solvent under catalyst- and additive free
operation.
Entry
Catalyst
Base
Solvent
T (ꢀC)
Yieldb (%)
1
2
3
4
5
6c
7
8
CuI
—
—
—
—
—
—
—
Cs2CO3
—
—
—
—
—
—
—
EL
EL
DMF
Toluene
EL
EL
EL
EL
110
110
110
110
90
90
60
40
57
55
52
15
68
24
90
19
a
General conditions: 10 mmol% CuI (when used) and 2 equiv. mole
Cs2CO3 (when used), 1.0 mmol thiol, 1.5 mL solvent and stirred for 12
b
c
Originally, we discovered the selective promotion of EL on
the dehydrogenative coupling of thiols during an attempt of
performing C–S coupling reactions of thiophenol 1a and iodo-
benzene 2. Interestingly, as shown in Scheme 1, no target
h
at open air. Yield of isolated product. The reaction was
performed in N2 atmosphere.
transformation of thioether 3 was observed in the presence of properties have been subjected for coupling reaction. The
CuI, cesium carbonate and 1,10-phenanthroline. Instead, results on synthesizing different disuldes using corresponding
disulde 4a was selectively provided at high yield (Scheme 1). thiols were outlined in Table 2. According to these results, those
Inspired by this interesting result, we therefore conducted frequently available thiols including aryl, heteroaryl as well as
further investigation on this transformation in hope of devel- alkyl functionalized ones could be smoothly transformed to
oping a green synthetic methodology for the synthesis of corresponding disuldes in this catalyst- and additive-free,
disuldes.
neutral system. Thiophenols containing para- and meta-
Firstly, following the original result, we examined the self- substituent all gave good to excellent yields in despite of the
coupling reaction of thiophenol 1a in EL in the presence of CuI electronic property of the functional group (entries 1–6, 8 and
and Cs2CO3 at 110 ꢀC, 53% yield of product 4a was provided 11, Table 2). As typical heteroaryl thiol, pyridine-2-thiol has also
(entry 1, Table 1). Interestingly, a control experiment without been coupled to give corresponding disulde 4l in excellent
using any catalyst and base in EL gave similar yield (entry 2, yield (entry 12, Table 2). The ortho- substituted thiophenols
Table 1), this results encouraged us to further examine other afforded lower yields of disuldes probably because of the bulky
parameters to enhance the yield without using any catalyst or hindrance effect of ortho- substituent (entries 7, 9 and 10, Table
additive. Reactions performed in polar solvent DMF, nonpolar 2). Finally, aliphatic thiols such as benzylthiol and octylthiol
solvent toluene at 110 ꢀC both gave lower yield (entries 3 and 4, have also been coupled to afford corresponding disuldes 4m
Table 1). Investigation on different reaction temperatures sug- and 4n in satisfactory yields, too (entries 13 and 14, Table 2). All
gested that 60 ꢀC gave the best yield (entries 5, 7 and 8, Table 1). disulde products synthesized in our experiment have been
It was notable that identical reaction performed in N2 atmo- characterized by 1H and 13C NMR, and the structures have been
sphere gave a yield of 40% product probably enabled by the clearly assigned by comparing NMR data with those reported in
small amount of oxygen solved in EL (entries 6, Table 1).
literature. As typical example, The E-factor for the synthesis of
With the in hand results on optimization, we then performed 4b (entry 2, Table 2) has been calculated as 13.1 kg kgÀ1 (see ESI
further investigation to examine the application scope of the for calculation†), demonstrating the comparable environmental
present protocol. A variety of thiols of different structures and friendliness of our method with most previously reported
methods.38,39
Based on the promotion effect of EL to this S–S coupling
process, we performed control experiments to probe the
possible factor that enables the transformation. Since oxygen
was the oxidant of the reaction, it was possible that the solu-
bility of reaction medium to oxygen played the main role in the
reaction. Therefore, the model reaction were performed under
oxygen atmosphere in toluene and EL, respectively.40 In the
experiments, the entry performed in EL completed rapidly to
afforded product 4a in 94% yield in the reaction time of 2 h,
while equivalent entry performed in toluene afforded 4a only in
Scheme 1 Selective S–S coupling reaction mediated by EL.
21370 | RSC Adv., 2013, 3, 21369–21372
31% yield even aer the reaction time of 6 h (Scheme 2). The
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Table 2 Synthesis of various disulfides via catalyst- and additive free coupling of
thiolsa
Table 2 (Contd. )
Entry
11
R
Product
Yieldb (%)
Entry
1
R
Product
Yieldb (%)
Naphth-2-yl
79
Ph
90
2
3
4
5
6
7
8
4-MeC6H4
4-i-PrC6H4
4-FC6H4
97
93
91
87
86
67
94
12
13
Pyridine-2-yl
PhCH2
95
77
74
14
n-C8H17
a
General conditions: 1.0 mmol thiol, 1.5 mL EL and stirred at 60 ꢀC for
b
12 h. Yield of isolated product.
4-ClC6H4
4-BrC6H4
2-MeC6H4
3-MeC6H4
Scheme 2 Different solvents for thiophenol coupling under oxygen.
results implied that oxygen has much higher solubility in EL
than toluene. Therefore, it was rational to conclude that the
oxygen solved in EL acted as the oxidant and dominantly
promoted the oxidative dimerization of thiols.
Finally, In order to examine the application of disuldes in
organic synthesis, we subjected disulde product 4a to reaction
9
2-NH2C6H4
61
57
10
2-ClC6H4
Scheme 3 Synthesis of 2-thiobenzothiazoles using disulfide.
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21372 | RSC Adv., 2013, 3, 21369–21372
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