Natural gallic acid catalyzed aerobic oxidative coupling with the assistance of MnCO3 for synthesis of disulfanes in water

Article abstract of DOI:10.1039/c9gc00091g

The formation of S-S bonds has great significance and value in synthetic chemistry and bioscience. To pursue a sustainable approach for such a synthesis, an aerobic oxidative coupling method for the efficient preparation of organic disulfanes, using a low-toxic natural gallic acid as an organocatalyst, inexpensive MnCO₃ as a cocatalyst, O₂ as the terminal oxidant and water as the solvent, has been successfully developed. Such metal-organic cooperative catalytic protocol provided an access to various symmetrical and unsymmetrical disulfanes in up to 99% yield. Gram scale synthesis with practical convenience and low loading of catalysts further illustrates the practicability of our method.

Full text of DOI:10.1039/c9gc00091g

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DOI: 10.1039/C9GC00091G
Journal Name
ARTICLE
Natural Gallic Acid Catalyzed Aerobic Oxidative Coupling in
Assistance of Mn(CO3)2 for Synthesis of Disulfanes in Water†
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Lijuan Song, a Wenhao Li, a Wenxue Duan, a Jichao An, a Shanyu Tang, a Longjia Li, a and Guanyu Yang
a
*
www.rsc.org/
The formation of S-S bonds have great significance and value in synthetic chemistry and bioscience. To pursue a sustainable
approach for such synthesis, an aerobic oxidative coupling method for efficient preparation of organic disulfanes, using a
low-toxic natural gallic acid as an organocatalyst and inexpensive Mn(CO3)2 as a cocatalyst, O2 as the terminal oxidant and
water as the solvent, has been successfully developed. The multiple applications of this metal-organic cooperative catalytic
protocol access to various symmetrical and unsymmetrical disulfanes in up to 99% yield. Gram scale synthesis with practical
convenience and low loading of catalysts further illustrates the practicability of our method.
the oxidative coupling of thiols, which included transition
Introduction
16
metal-,14 and organo-15 and enzyme
catalytic models.
The disulfide bonds are extremely valuable functional group in
abundant natural compounds, biological agents and drugs that
display potent reactivity or biological activities.1-3 With
awareness of its biocompatibility, researchers often utilized
disulfide bonds as vital motifs in new drugs,4-6 and also in
prodrugs for drug delivery.7 Furthermore, disulfide group has
already played extensively multifaceted roles in functional
materials such as biological materials, biological chemosensors,
rechargeable batteries and rubber vulcanization accelerator,
etc.8-9 Although there are several less commonly used methods
for preparation of disulfanes (the IUPAC recommended
nomenclature of organic disulfides) such as thiolysis, reductive
dimerization of thiocyanates, alkyl halides substitution with
sulfur or polysulfide, reductive coupling of sulfonyl chlorides,
etc, the formation of disulfanes most generally occurs via
oxidative radical formation and subsequent dimerization of
thiols.10-12 However, the oxidative coupling with stoichiometric
oxidants is still used in manufacture of some industrial
disulfanes. For example, 2-mercaptobenzothiazole (1a) is
oxidized with NaClO or NaNO2 for the industrial manufacture of
2,2’-disbenzothiazole disulfide (2a), a widely used vulcanization
accelerator in the rubber industry and a pharmaceutical
intermediate in antibiotics production, which produces large
quantities of liquid waste that contains a large percentage of
salt and nitrogen oxides, and thus suffers from high cost of
disposal.13 Therefore, many catalysts have been discovered for
using molecular oxygen as environmentally friendly oxidant for
Unfortunately, while the oxidative self-coupling of thiols results
in the formation of symmetrical disulfane, the synthesis of
unsymmetrical disulfane via catalytic cross-coupling of different
thiols is indeed a subtle methodological challenge. Recent
reports gave two an alternative pathway to unsymmetrical
disulfane, which were called electro-oxidative cross-coupling 17
and copper-catalyzed oxidative cross-coupling of arylboronic
acid and RSSAc,18-21 respectively. However, the former is only
suitable to synthesize aryl alkyl disulfanes, and the latter uses a
special disulfurating reagent. Accordingly, the development of
the methods for constructing disulfide bond via oxidative
coupling has emerged as a research area of significant
importance.
While some respectable achievements in synthesis of
disulfanes have been made, sustainable technologies are still
required with respect to environmental concerns, safety, and
cost, facile workup, as well as practical industrial application.
Undoubtedly, aqueous aerobic oxidation is a hopeful one
because of the using both of the most green and cheap solvent
and oxidant.22-24 These aspects motivated us to pursue a more
efficient and practical oxidative coupling for direct catalytic
synthesis of disulfanes using molecular oxygen as the terminal
oxidant and water as the onefold solvent.23-28 In consideration
of the mechanisms both of aerobic oxidation and thiols
coupling, our target catalytic system should be reasonable to
deduced two components: 1) a water-soluble redoxable
catalyst whose oxidation state could abstract H from thiol to
give the thiyl radical, 2) a redoxable metal ion responsible for
activating the molecular oxygen and oxidizing the reduction
state of catalyst to its oxidation state.
a. College of Chemistry and Molecular Engineering, Zhengzhou University,
Zhengzhou, 450001, China. E-mail: yangguanyu@zzu.edu.cn.
†Electronic Supplementary Information (ESI) available: Supporting information and
the ORCID identification number for the author of this article. See
DOI: 10.1039/x0xx00000x
Moreover, the utilization of renewable fedstocks is deemed
to be the indicator of chemical sustainability.29 Phenolic acids,
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DOI: 10.1039/C9GC00091G
especially multihydroxyl ones, are abundant biomass feedstock ion showed bare influence on the reaction (entries 13-16),
that can be derived from plant biomass materials. Much of whereas Fe, Cu and Co salts with various anions showed
them display antioxidant activities and protective effects different catalytic activities (entries 1-12). Moreover, it was
against chronic diseases and so on, mainly because of single notable imperatively that some amounts of benzothiazole as a
electron redox property of their hydroxyl moieties.30-32 So they byproduct were found in all catalytic reactions of Fe, Cu and Co
were thought to be our target redoxable organocatalyst, and salts, respectively (as determined by HPLC and GC-MS).
their water solubility, readily availability, low toxicity and Fortunately, such dethiolation of 1a did not occur in all cases of
biodegradability could lead the establishment of greener and Mn catalysis, and HAS/Mn was found to be a quite effective
cleaner chemical processes for disulfanes preparation in water. catalytic system.
Therefore, by selecting a multihydroxyl phenolic acid as the
It should be notable that Mn is a earth-abundant metal, and
catalyst, we herein investigated a metal-organic cooperative MnCO3 exists naturally as the mineral rhodochrosite.33 Its
catalytic protocol in aerobic oxidative coupling of thiols for readily availability and inexpensiveness make this metal-organic
disulfane synthesis. As far as we are aware, phenolic acid as the cooperative catalytic protocol to have more applicable
sole organocatalyst was applied here for the first time to potential.
mediate efficiently the aerobic oxidative coupling of thiol.
Catalytic abilities of various phenolic acid
Various phenolic acid (0.5 mol%) were employed to catalyzed
the aerobic oxidative coupling of 1a in the present of 0.2 mol%
Results and discussion
Screening of metal cocatalyst
MnCO3 (Table 2). Salicylic acid with sole hydroxyl moiety gave a
poor yield (entry 1), but multihydroxyl phenolic acids had higher
catalytic activities(entries 2-8). Among them, ones with para-
dihydroxyls display generally much better catalytic
performance than that with two hydroxyls at the ortho-, or
Our initial attempt at the catalytic synthesis of disulfane
explored the performance of common metal salts. Therein, the
self-coupling of 1a was used as the model reaction and 5-
Hydroxy-salicylic acid (HSA) as the organocatalyst (0.5 mol%)
with 0.5 mol% transition metal salts in water under 0.3 MPa O2
at 80 oC for 3 h (Table 1). As can be seen, the aerobic oxidative
meta-position.
And
gallic
acid
(GA)
and
2,5-
dihydroxyterephthalic acid realized excellent yields,
respectively (entries 7-8).
Table 1. Aerobic oxidative coupling of 1a with HSA and various metal salts.a
Table 2. Aerobic oxidative coupling of 1a with MnCO3 and phenolic acids. a
HO
COOH
N
S
0.5 mol%
S
N
S
N
S
Entry
Phenolic Acid or Quinone
HPLC Yield (%)
OH
S
SH
0.5 mol% Metal Salt
1
2-OH-COOH
12
23
22
66
19
69
94
96
61
60
15
11
7
1
2a
2
2,4-di-OH-COOH
Entry
Metal salt
HPLC Yield (%)
3
2,3-di-OH-COOH
1
FeSO4
17
57
27
19
54
71
52
44
58
51
56
44
79
75
77
78
4
2,5-di-OH-COOH
2
Fe2(SO4)3
NH4Fe(SO4)2
FeCl3
5
2,4,6-tri-OH-COOH
2,3,4-tri-OH-COOH
3,4,5-tri-OH-COOH
2,5-di-OH-1,4-di-COOH
1,4-benzoquinone
1,4-benzenediol
3
6
4
7
5
CuCl2
8
6
CuSO4
9
7
Cu(OAc)2
CuCO3
Co(OAc)2
CoSO4
10
11
12
13
14
15 b
16 b
8
1,2-benzenediol
9
1,3-benzenediol
10
11
12
13
14
15
16
1,3,5-benzenetriol
2,5-di-OH-1,4-benzoquinone
2,5-di-OH-1,4-benzoquinone
1,4-benzoquinone
CoCl2
18
79
76
CoCO3
MnCl2
MnSO4
MnCO3
Mn(OAc)2
a
Reaction conditions: 1a (3.34 g, 20 mmol), MnCO3 (0.2 mol%),
Phenolic Acid (0.5 mol%), 50 mL H2O, pH = 9, 80 oC, 0.3 MPa O2, 5
h. b CH3CN instead of H2O.
a Reaction conditions: 1a (0.5 mmol), HSA (0.5 mol%), metal salt (0.5
mol%), 3 mL H2O, pH = 9, 80 oC, 0.3 MPa O2, 3 h.
It is well documented that quinones, due to their two single
electron redox cycles between itself and its corresponding
semiquinone or hydroquinone, could realize oxidations.34-39
As contrasted with phenolic acids, some quinones, and the
corresponding polyphenols were also tested (entries 9-14). 1,4-
coupling of 1a proceeded in all case. However, the different
metal salts gave different yields of 2a. In contrast, Mn salts
displayed better than Fe, Cu and Co. And the counterions of Mn
2 | J. Name., 2012, 00, 1-3
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Benzenediol and p-benzoquinone obtained similar modest amounts of both GA and MnCO3 resuDltOedI: 1i0n.10f3a9s/tCe9rGrCa0t0e0s91oGf
yields (entries 9-10), meaning that the organocatalysts coupling (entries 1–8). However, the influence of the loading
underwent
the
redox
cycles
of
quinone- amount of GA on the rate was obviously stronger than that of
(semiquinone-)hydroquinone during the aerobic oxidative MnCO3. And 0.15 mol% seemed to be the preferable loading
coupling of thiol. However, 1,2- and 1,3-Benzenediol as well as amounts of both GA and MnCO3, meaning the ratio of them was
o
1,3,5-Benzenetriol gave
a
lower yields (entries 11-13). 1. The data of entries 6 and 11–13 showed that at 80 C the
Surprisingly, the coupling occurred less effectively when 2,5- coupling proceeded so rapidly that a near complete conversion
dihydroxyl-1,4-benzoquinone was used (entries 14). The reason was obtained after 4 h. Beyond 4 h, there was no significant
probably is that two intramolecular hydrogen bonds between increase in yield, probably due to the very low concentration of
its hydroxyls and carbonyls restrained its oxidation. The 1a in the reaction mixture. Increasing the reaction temperature
catalytic activities of 2,5-dihydroxyl-1,4-benzoquinone and p- increased the coupling rate, and the preferable temperature
benzoquinone increased obviously, albeit in modest yields, was 80 oC (entries 6, 9-10). The pressure of O2 showed a positive
when the reactions conducted in CH3CN instead of H2O (entries influence on the rate below 0.3 MPa (entries 14-16). This
15-16). This implied that lower aqueous solubility of quinones suggested that the rate of coupling is controlled by molecular
limited their catalytic performances in water.
oxygen diffusion and solution in water media under the lower
As a contrast, the renewable, inexpensive and low-toxic GA pressure. Moreover, the oxidations barely occurred in the
(LD50 rat = 5000 mg kg–1, the datum has been check with the absence of any component under the same conditions (entries
ChemSpider Database.) had higher aqueous solubilities due to 17-19), displaying that two components were indispensable.
its more than one hydrophilic hydroxyls and one hydrophilic
Consequently, under the optimal conditions disulfane
carboxyl moieties, therefore displayed perfect catalytic synthesis could realized perfect efficiency on gram scale, the
performances, as expected.
product 2a with over 99% purity could be obtained by simple
filtration after the reaction accomplishment. The practical
convenience and low loading of catalysts of our catalytic
method illustrated its practicability.
Reaction conditions optimization
In the further optimization of the reaction conditions, we
Self-coupling of various thiols
Table 3. Conditions Screening of 1a Self-coupling with GA and MnCO3. a
The optimal coupled system of GA and MnCO3 was employed
further to catalyze the aerobic oxidative self-coupling of various
thiols to the corresponding symmetric disulfanes (Table 4). As
Entry
GA
(mol%)
MnCO3
(mol%)
P
T
t
Yield
(%)b
(MPa)
(oC)
(h)
1
0.075
0.125
0.15
0.25
0.5
0.2
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.2
0.1
0.3
0.3
0.3
0.3
80
80
80
80
80
80
80
80
100
60
80
80
80
80
80
80
80
80
80
5
5
5
5
5
5
5
5
5
5
4
3
2
4
4
4
4
4
4
33
72
98
98
99
98
82
69
98
65
98 c
78
14
64
49
96
6
expected,
GA/MnCO3
displayed
exciting
catalytic
2
0.2
performances. Substituted thiophenols bearing electron-
donating groups (1b-j), such as amino, acetylamino, methyl,
hydroxyl, or methoxyl group, and electron withdrawing groups
(1k-p), such as chloro, bromo, carboxyl, nitro, or
methoxycarbonyl group, gave all desired disulfanes 2b-p in
excellent yields, and substiuents, whatever in the ortho-, meta-
or para-position of thiophenols, showed no significant
difference effects on the yields. Naphthyldisulfane 2q was
synthesized in 99% yield. Heteroaromatic thiols, such as 1a,
thiophene-2-thiol, pyridine-2-thiol, and pyrimidine-2-thiol,
were all oxidized to the corresponding disulfanes 2a and 2r-t
with good to excellent yields, respectively. And also the
oxidation of benzylthiol gave 93 % yield of 2u. In contrast, the
self-coupling of aliphatic thiols proceeded slowly. In the course
of 4 h, the oxidative couplings of cyclohexanethiol and n-
hexanethiol (1v-w) gave 39% and 44% yields of the
corresponding disulfanes (2v-w), respectively. Nevertheless,
the yields of 2v-w can be promoted apparently by merely
prolonging the reaction time. Consequently, this oxidative self-
coupling of thiols in the aqueous phase is highly versatile and
efficient for the synthesis of a large variety of symmetric
disulfanes.
3
0.2
4
0.2
5
0.2
6
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0
0.15
0.125
0.1
7
8
9
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0
10
11
12
13
14
15
16
17
18
19
0.15
0
14
4
0
a Reaction conditions: 1a (3.34 g, 20 mmol), 50 mL H2O, pH = 9. b HPLC
yield. c Isolated yield.
evaluated both the loading amounts of GA and MnCO3,
temperature, O2 pressure, and reaction time (Table 3). As can
be seen, the coupled system can work even at as low as ca 0.075
mol% loading of GA, giving 33% conversions in the course of 5 h
(entry 1). It was not unexpected to find that the more loading
Table 4. Synthesis of symmetric disulfanes by GA and MnCO3.a,b
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GA
It should be pointed that under the abDoOveI: 1o0p.1t0im39a/Cl c9oGnCd00it0io91nGs
the occurrence of self-coupling was not prevented completely
and a few of symmetrical disulfanes often existed. So, variations
on the reaction conditions had been conducted. When 2 equiv.
R1SH was used without the other conditions
0.15 mol%
S
R
R
SH
R
S
0.15 mol% MnCO3
1
2
NH2
N
S
S
S
N
H2N
S
S
S
S
S
NH2
H2N
2a (98%)
2b (96%)
2c (97%)
H2N
S
S
S
S
S
S
NHAc
NH2
AcHN
Table 5. Synthesis of unsymmetric disulfanes with GA and MnCO3. a,b
2d (98%)
2e (97%)
2f (98%)
GA
0.15 mol%
S
R1
OH
R
SH
R1 SH
R
S
S
S
S
S
S
S
0.15 mol% MnCO3
3
HO
2g (96%)
2h (99%)
2i (92%)
Br
OCH3
Cl
S
S
S
Br
S
4
S
S
S
S
S
S
S
S
H2N
H2N
H2N
H3CO
Cl
3a (93%)
3b (90%)
3c (91%)
2j (96%)
2k (94%)
2l (98%)
NO2
N
S
N
S
COOH
S
S
S
S
COOH
S
S
COOH
S
N
S
S
S
c
d
c
d
c
d
3d (59%, 97% , 97% ) 3e (72%, 84%, 96% )
3f (56%, 88%, 92% )
S
O2N
HOOC
2m (96%)
CO2Me
2n (98%)
2o (97%)
S
S
S
S
S
S
S
H3CO
S
S
HOOC
AcHN
S
S
S
c
d
d
d
S
3g (57%,89% , 93%
)
3h (61%, 78% )
3i (71%, 90%
)
CO2Me
S
2p (97%)
2q (99%)
2r (81%)
S
S
NH2
S
S
H2N
S
N
N
S
S
S
N
S
S
S
N
S
N
N
N
d
d
d
3j (68%, 96%
)
3k (58%%, 96%
)
3l (63%, 98% )
2s (99%)
2t (77%)
2u (93%)
S
S
S
N
S
S
S
S
S
S
S
N
O2N
4
4
d
d
d
3m (53%, 77% )
3n (20%, 88% )
3o (96% )
c
c
2v (39%, 67%
)
2w (44%, 71% )
a Reaction conditions: 1a (0.5 mmol), 3 mL H2O, pH = 9, 80 oC, 0.3 MPa
O2, 4 h. b Isolated yield. c For 18 h.
S
S
S
S
S
S
4
N
HOOC
HOOC
3p (91% [d]
)
3q (91% [d]
)
3r (94% [d]
)
S
S
S
S
N
S
4
4
Cross-coupling of various thiols
S
N
N
S
d
d
d
Although there are many different methods for the preparation
of symmetrical disulfanes, most of them are not suitable to the
synthesis of unsymmetrical disulfanes, due to the formation of
symmetrical side products form self-coupling. The
stoichiometric oxidation of mixtures of thiols, and thiol-
disulfane exchange reactions are the most common approaches
to obtain unsymmetrical disulfanes.40 An interesting oxidation
method used dichlorodicyanoquinone (DDQ, 1 eqiv.) as oxidant,
which afforded moderate to high yields of unsymmetrical
disulfanes with equimolar loading amounts of different thiols,
but it did not tolerated the presence of amino group at thiol
probably due to reaction with carbonyl of DDQ, and failed to
oxidize the tertiary thiol possibly due to steric hindrance.38, 41 To
expand the generality of GA/MnCO3 method for cross coupling,
a series of mixtures of different thiols were tested (Table 5). It
was delightful to find that, in the course of 4 h the cross
couplings of p-aminophenthiol with t-butylthiol, n-hexylthiol,
and cyclohexylthiol in equimolar amounts realized 93%, 90%,
91% isolated yield (3a-c), respectively. This meant that
GA/MnCO3 tolerated amino thiol and the tertiary thiol
oxidation. Furthermore, the cross couplings of t-butylthiol with
various aryl thiols obtained good yields of unsymmetrical
disulfanes (3d-n), respectively.
3s (95%
)
3t (94% )
3u (92% )
NH2
S
S
S
S
S
NH2
S
N
S
O2N
H2N
d
d
d
3v (85% )
3w (85% )
3x (84%
)
Cl
N
S
S
S
S
H2N
H2N
d
d
3y (79%
)
3z (71% )
a Reaction conditions: RSH (0.5 mmol), R1SH (0.5 mmol), GA (0.28 mg,
0.15 mol%), MnCO3 (0.172 mg, 0.15 mol%), 3 mL H2O, pH = 9, 80 oC,
0.3 MPa O2, 4 h. b Isolated yield. c 1.0 mmol R1SH was used. d 1.0 mmol
Na2CO3 was used.
change, the cross-coupling became the main reaction (3d-g).
Excitingly, 2-Pyridyl t-butyl disulfanes was obtained in 97% yield (3d).
The cross-couplings of t-butylthiol with pyrimidine-2-thiol and
thiophene-2-thiol gave 84% and 88% yields, respectively (3e-f).
Further conditions screening indicated that alkalinity shown positive
effect markedly on formation of unsymmetrical disulfanes. When 1
equiv. Na2CO3 was added into the reaction mixture instead of pH 9
adjustment, the yields of unsymmetrical disulfanes promoted
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tremendously. The cross-couplings of heteroaromatic thiols, benzenediol were not observed when thDioOlIw: 1a0s.10a3d9d/Ce9dGiCn0to0019,14G-
arylthiols and alkylthiols gave over 90% yields of the corresponding benzenediol solution (d, A, Figure 2), meaning 1,4-benzenediol
unsymmetrical disulfanes (3d-u), respectively, where the oxidation was restrained completely. The similar phenomenon
symmetrical disulfanes were barely found. Good yields were realized also was observed in the HPLC tracing tests on interactions of
in the cross-couplings between the different arylthiols (3v-z). GA and 4-methoxy-phenthiol (B, Figure 2). Along with the
Although the reason of the alkalinity effect should be further studied, amount of 4-methoxy-phenthiol decreased, the corresponding
it didn't make any difference to the conclusion that a novel and disulfane (5.80 min) increased, but any GA oxidation was not
simple method of unsymmetrical disulfanes synthesis was developed. found (d-e, B, Figure 2). These meant that thiol could
immediately reduce the inchoate oxidation product of
Studies of aerobic oxidative coupling routes
Recognizing the successful performance of the first
combination of GA and MnCO3, we sought to find the route
which both of phenolic acids and Mn ion went through in the
oxidative coupling.
It is well documented that hydroquinone oxidation featured two
readily accessible oxidation states: one-electron-oxidized
semiquinone, and two-electron-oxidized quinone.36 Both of them
could oxidize other substrate via single electron transfer and
converted to their reducing states. In-situ UV investigation indicated
clearly that p-benzoquinone was reduced to 1,4-hydroquinone
during its reaction with t-butylthiol under N2 atmosphere (Blue line,
Figure 1). Being identical to the reference samples, the shoulder peak
at 239 nm was assigned to the absorption band of p-benzoquinone,
and its absorbance decline meant that p-benzoquinone was
somewhat reduced during its reaction with t-butylthiol.
Figure 2. HPLC tracing tests on interactions of 1,4-hydroquinone and GA
with thiols at room temperature. A) 1,4-Hydroquinone (2×10-6 mol/ml) and t-
butylthiol (2×10-5 mol/ml), the flow phase CH3OH/H2O (v:v = 1:1), the
detection wavelength 230 nm; p-Benzoquinone (2×10-6 mol/ml). B) GA
(1.3×10-6 mol/ml) and 4-methoxy-phenthiol (1.3×10-5 mol/ml), the flow phase
CH3OH/H2O (v:v = 9:1), the detection wavelength 254 nm.
Figure 1. In-situ UV investigation on reaction of 1,4-benzoquinone and t-
butylthiol in CH3CN at 70 oC under N2 atmosphere for 3 h, all concentrations
were 1×10-7 mol/ml except for the mixture of 1,4-benzoquinone (5×10-8
mol/ml) and 1,4-hydroquinone (4×10-8 mol/ml).
We noticed that the colorless aqueous solution of 1,4-
benzenediol became red at once when its pH was adjusted to 9
at room temperature. After stirring for 10 min ca 10% p-
benzoquinone was found in the solution by HPLC detections,
and the amount of 1,4-benzenediol continuously decreased
when the time prolonged (A, Figure 2), showing that the 1,4-
benzenediol was converted to the corresponding phenolic
anion and then readily susceptible to oxidation to
benzoquinone and over-oxidation products. In sharp contrast,
any changes both of solution color and the amount of 1,4-
phenolic acid as long as it formed. So it may be speculated that
in phenolic acid catalysis the reciprocal transformation between
hydroquinone and semiquinone was the main redox cycle,
quinone barely existed.
Inorder to understand why unsymmetrical disulfanes were
the major products one when 1 equiv. Na2CO3 was used, HPLC
tracing tests on reactions between equimolar 2t and t-butylthiol
was operated under the optimal conditions (Figure 3). The
results clearly clarified that the formation of unsymmetrical
disulfanes followed the formation of symmetrical disulfanes,
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meaning that unsymmetrical disulfane was produced by
thiolate-disulfane exchanged reaction.41-42 In comparison of the
results of reaction at pH9 (a - c, Figure 3) and using 1 equiv.
Na2CO3 (d - e, Figure 3), it could be concluded that alkalinity
accelerated this thiolate-disulfane exchanged reaction.
Conclusions
We successfully developed a novel, highly efficient and versatile
methodology to prepare disulfanes that used firstly a natural
renewable gallic acid as an organocatalyst, inexpensive
Mn(CO3)2 as a cocatalyst, dioxygen as the terminal oxidant and
water as the onefold solvent. Mechanistically, the reciprocal
transformation between hydroquinone and semiquinone of
phenolic acid was possibly the key catalytic redox cycle that lead
thiol more easily to thiyl radical and then coupled to disulfane.
Such aerobic oxidative coupling method was suitable to
synthesize various disulfanes from aromatic, alkyl, and
heterocyclic thiols under mild condition, and tolerated amino
thiol and the tertiary thiol. Importantly, unsymmetrical
disulfanes were prepared with high yields from directly the
corresponding mixture of two different thiols in equimolar
amounts. The reaction can be conducted on a gram scale with
good reaction efficiency, which gives a practicable protocol
from both an economic and an environmental point of view as
well as for operational ease of not handling organic solvents,
toxic and expensive reagents. Further application of this general,
straightforward and sustainable approach in other useful
transformations is under way in our laboratory.
Figure 3. HPLC tracing tests on the reactions between equimolar 2t and t-
butylthiol at 80 oC. 4.02 min, 2t; 10.81 min, 3e. The flow phase CH3OH/H2O
(v:v = 6:4), the detection wavelength 254 nm.
Since there are easy redox transformations during the
multivalence states, Mn and its oxides have been extensively
employed as a component in the oxidation catalysts.43-46 In our
catalytic system, Mn2+ combined affinitively with dioxygen to
form the active MnO species that was responsible for activation
of dioxygen and transmit oxidizability to the oxidation of
phenolic acid.
As a consequence, although MnO species are not known in
detail, the general mechanism of this new catalytic oxidative
coupling can be described possibly as in Scheme 1. Under basic
condition, thiol converted to the corresponding thiolate anion.
During the reaction, phenolic anion was oxidized to its
semiquinone radical by MnO species. The transformation of
semiquinone radical to hydroquinone anion converted the
thiolate anion easily to the thiyl radical which then coupled to
symmetrical disulfane. Another thiolate anion reacted with
symmetrical disulfane to give unsymmetrical one.
Experimental Section
General Procedure for the Aerobic Oxidative Self-Coupling
The catalytic reactions were performed in a 25-mL Schlenk tube and
the general procedure is described typically with self-coupling of 2-
mercaptobenzothiazole (1a) as follows: 1a (0.5 mmol), gallic acid
(GA) (0.15 mol%), MnCO3 (0.15 mol%), and H2O (3 mL) was added
into the reactor and adjusted pH to 9 by Na2CO3 solution under
stirring. Subsequently, the reaction mixture was stirred under 0.3
MPa O2 at 80 oC and monitored by thin layer chromatography (TLC).
After cooling to room temperature, the end reaction mixture was
added 10 mL water to and extracted with ethyl acetate (10 mL×3).
The combined organic extract phase was dried over Na2SO4, and
after filtration, the solvent was removed on rotovap under reduced
pressure. The resulting residue was purified by flash chromatography
on silica gel to give the desired product.
General Procedure for the Aerobic Oxidative Corss-Coupling
O
RSH (0.5 mmol), R1SH (0.5 mmol), GA (0.15 mol%), MnCO3 (0.15
mol%), Na2CO3 (1.0 mmol) and H2O (3 mL) was added into a 25-
mL Schlenk tube. Other subsequent operations were
in keeping with the above procedure of self-coupling.
COO
Mn4+
O
R
S
O
O
S
R
R
S
O
Mn2+
Conflicts of interest
There are no conflicts to declare.
O2
COO
R
S
H2O
R1
S
R
S
R1
S
Acknowledgements
R
S
R
S
R
S
Scheme 1. The proposed route of Mn-mediated phenolic acids-catalyzed The authors would thank Research Fund of Henan Industry-
aerobic oxidative coupling of thiols under basic condition.
6 | J. Name., 2012, 00, 1-3
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