PdCl2/DMSO-Catalyzed Thiol-Disulfide Exchange: Synthesis of Unsymmetrical Disulfide

Article abstract of DOI:10.1021/acs.orglett.1c00858

Unsymmetrical disulfides have been effectively prepared through thiol exchange with symmetrical disulfides employing a simple PdCl2/DMSO catalytic system. The given method features excellent functional group tolerance, a broad substrate scope, and operational simplicity. This reaction is especially useful for late-stage functionalization of bioactive scaffolds such as peptides and pharmaceuticals. Disulfide-containing organic dyes have also been prepared. This transformation could be extended to thiol-diselenide or thiol-ditelluride exchange affording RS-SeR′ or RS-TeR′.

Full text of DOI:10.1021/acs.orglett.1c00858

pubs.acs.org/OrgLett
Letter
PdCl2/DMSO-Catalyzed Thiol−Disulfide Exchange: Synthesis of
Unsymmetrical Disulfide
Jimin Guo, Jianjian Zha, Tao Zhang, Chang-Hua Ding, Qitao Tan,* and Bin Xu*
Cite This: Org. Lett. 2021, 23, 3167−3172
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ABSTRACT: Unsymmetrical disulfides have been effectively
prepared through thiol exchange with symmetrical disulfides
employing a simple PdCl2/DMSO catalytic system. The given
method features excellent functional group tolerance, a broad
substrate scope, and operational simplicity. This reaction is
especially useful for late-stage functionalization of bioactive
scaffolds such as peptides and pharmaceuticals. Disulfide-
containing organic dyes have also been prepared. This trans-
formation could be extended to thiol−diselenide or thiol−
ditelluride exchange affording RS−SeR′ or RS−TeR′.
isulfides are prevalent in life science,1 natural products,2
that is essential for cell growth and function.6 Many potent
bioactive natural products such as members of the antifungal
polycarpamine family2 contain disulfide bonds. Sulfur−sulfur
bonds are also prevalent in marketed drugs such as
romidepsin,3 lipoic acid,7 disulfiram,8 octreotide,9 and
atosiban.10 The disulfide bonds have also been extensively
utilized as linkers in antibody−drug conjugates (ADCs) to
deliver the active drug to the targeted cell after cleavage.11 In
food chemistry, ajoene, a major biologically active constituent
of garlic, also contains a disulfide bond.4 In materials science,
industrially important polymers such as rubber contain
disulfide bonds. Disulfides have been incorporated into
polycyclic aromatic hydrocarbons, leading to novel photo-
electric materials5 such as persulfurated coronene, which is a
promising cathode material for lithium−sulfur batteries.
D
pharmaceuticals,3 food chemistry,4 and materials sci-
ence5 due to their unique pharmacological and physiochemical
properties (Figure 1). For instance, disulfide bonds play a vital
Given the importance of unsymmetrical disulfides in many
fields, their synthesis has received considerable attention.12
However, the synthesis of unsymmetrical disulfides is still
challenging in terms of efficiency and selectivity. Unsym-
metrical disulfides can be synthesized by the oxidative cross
coupling of two different thiols in the presence of oxidants,13
through electro-oxidation or photoredox catalysis (Scheme
1a).14 The substitution reaction between a thiol and a
prefunctionalized thiol with a leaving group (LG) is an
effective method for constructing disulfides (Scheme 1b).15
Recently, metal-catalyzed cross-coupling or substitution
Figure 1. Representative disulfides.
role in the formation and stabilization of the secondary and
tertiary structures of proteins and thus are widely involved in
diverse biochemical processes.1 In cells, endogenously
abundant glutathione (GSH) can be oxidized to glutathione
disulfide (GSSG), and the reverse process is realized in the
presence of the NADPH-dependent enzyme glutathione
reductase, which maintains the cellular redox homeostasis
Received: March 15, 2021
Published: April 2, 2021
https://doi.org/10.1021/acs.orglett.1c00858
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3167−3172
3167

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a
Scheme 1. Pathways for Synthesizing Unsymmetrical
Table 1. Optimization of the Conditions
Disulfides
b
entry
catalyst
solvent
DMSO
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
9
Cu(OAc)2
Cu(TFA)2
CuCl2
CuCl
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
100
80
80
17
<5
<5
10
<5
10
<5
85
92
59
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
toluene
MeCN
NMP
1,4-dioxane
DMSO
DMSO
DMSO
DMSO
CuI
Pd(PPh3)4
Pd(OAc)2
Na2PdCl4
PdCl2
PdCl2
−
PdCl2
PdCl2
PdCl2
PdCl2
c
10
d
11
12
13
14
15
16
17
18
<5
<5
<5
<5
26
12
53
81
83
84
PdCl2
PdCl2
PdCl2
PdCl2
e
19
20
f
PdCl2
a
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), catalyst (0.025
mmol) in DMSO (2.0 mL), 80 °C, under a N2 atmosphere, 2 h.
b
c
d
Isolated yield. With 0.5 mmol of 2a. Ninety percent of 1a was
e
f
recovered. Air atmosphere. O2 atmosphere.
approaches with nucleophilic or electrophilic disulfurating
reagents have been developed (Scheme 1c).16 In 2019,
tetrasulfides were reported to undergo homolytic substitution
by alkyl radicals, enabling the synthesis of a broad range of
unsymmetrical disulfides (Scheme 1d).17 Rhodium-catalyzed
exchange reaction of two symmetrical disulfides provided
another route for the construction of unsymmetrical disulfides
(Scheme 1e).18 Thiol−disulfide exchange reaction is an option
for the synthesis of disulfides. Actually, thiol−disulfide
exchange has been involved in biological and self-healing
systems.19 Activated disulfides represented by bis(pyridin-2-yl)
disulfide have been frequently utilized for the synthesis of
unsymmetrical disulfides through a successive two-step
substitution reaction (Scheme 1f).19 As a part of our
continuing research on chalcogen chemistry,20 we herein
report a PdCl2/DMSO-catalyzed thiol−disulfide exchange for
the expedient synthesis of unsymmetrical disulfide with a broad
substrate scope and excellent functional group tolerance under
simple and mild conditions. This method demonstrates
significant advantages as it can be utilized to prepare peptide
disulfides,21 pharmaceuticals, and organic dyes without
protecting free amines, alcohols, and carboxylic acids.
The reaction conditions were optimized on the basis of the
model reaction of 2-mercaptobenzothiazole 1a with dimethyl
disulfides 2a (Table 1). Initial attempts employing Cu(OAc)2
as the catalyst and DMSO as the solvent at 80 °C afforded the
desired product 3a in 17% yield (entry 1). Other copper salts
as catalysts gave little or a trace amount of the desired product
(entries 2−5). Then, we investigated palladium catalysts in
terms of this transformation. Although Pd(PPh3)4 and
Pd(OAc)2 gave very low yields (entries 6 and 7, respectively),
Na2PdCl4 afforded the desired product in 85% yield (entry 8).
Replacement of expensive Na2PdCl4 with PdCl2 afforded the
desired product in 92% yield (entry 9). Reducing the amount
of 2a to 1.0 equiv resulted in a decreased yield, and the
byproduct 2-benzothiazyldisulfide (2p) from 1a was isolated in
32% yield (entry 10). Interestingly, most of 1a was recovered
using copper salts or in the absence of the palladium catalyst.
No product was obtained in the absence of a catalyst (entry
11). Among the solvents screened, DMSO is the sole solvent
that could afford appreciable yields (entries 12−16).
Decreasing or increasing the temperature caused decreased
yields (entry 17 or 18, respectively). The atmosphere only
slightly affected the yields (entries 19 and 20).
The substrate scope of thiols was next investigated (Scheme
2). Various mercapto five- or six-membered heterocycles gave
the desired products in moderate to excellent yields (3b−3f).
To our delight, thiophenols also exhibited good reactivity
under the reaction conditions (3g−3l). The structure of 3j was
unambiguously confirmed by single-crystal X-ray diffraction
analysis (Figure S1). The reaction exhibited excellent func-
tional group tolerance as the substrate containing free hydroxyl
and amino groups gave the desired products in good yields (3i,
3k, and 3l). Expectedly, naphthalene-2-thiol also gave
unsymmetrical disulfide 3m in moderate yield. Interestingly,
alkyl thiols were also suitable for this transformation (3n−3p).
Next, the scope of the symmetric disulfides was investigated
(Scheme 3). In general, aryl disulfides bearing electron-
donating and electron-withdrawing groups were tolerated and
afforded the desired products in good to excellent yields (4b−
4h). Heteroaryl disulfides could also give the desired products
(4i and 4j). Primary and secondary alkyl disulfides (4k−4o)
were suitable for this transformation. However, the reaction of
1a with sterically hindered tert-butyl disulfide could not give
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a,b
Scheme 2. Substrate Scope of Thiols
Scheme 4. Further Exploration of the Reaction Scope
a
Reaction conditions: 1 (0.5 mmol), 2a (1.0 mmol), PdCl2 (0.025
mmol) in DMSO (2.0 mL), 80 °C, 2 h, under a N2 atmosphere.
b
c
d
Isolated yield. 2a (2.5 mmol), 12 h. 2a (2.5 mmol).
a,b
Scheme 3. Substrate Scope of Disulfides
Considering the existence of free amine and carboxylic acid
groups in these compounds, excellent functional group
tolerance is a prerequisite.
To our delight, our method proved to be suitable for this
purpose. L-Cysteine was transformed into 7 in 62% yield
without a protecting group under mild conditions (40 °C). L-
Cysteine methyl ester and Boc-protected L-cysteine gave 8 and
9 in 78% and 68% yields, respectively. A glutathione derivative
could also be functionalized to give disulfide 10 in 77% yield.
Captopril, a potent inhibitor for the treatment of hyper-
tension,23 was successfully functionalized by this method. We
then applied this method for the synthesis of pyrene24 and 4,4-
difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY)25-based
dyes 12 and 13 (Scheme 4e). BODIPY dye 13 exhibits strong
emission both in solution (yellow) and in the solid state (red)
(Figures S3−S6).
Several control reactions indicate that PdCl2 catalyzed the
formation of disulfide 2p from 1a, and the thiol−disulfide
exchange is reversible under the reaction conditions (Figure
S2). Both alkyl and aryl disulfides with different S−S bond
dissociation energies exchange with 1a effectively. On the basis
of the experiments and literature, we proposed a possible
mechanism for this reaction (Scheme 5). We and others have
revealed that the DMSO/PdCl2 catalytic system is unique for
thiol transformations, in which DMSO plays vital roles as an
oxidant, ligand, and solvent.20a,26 First, ligand exchange
between PdCl2 and RSH gives a complex A, in which
DMSO might act as a ligand.27 Reductive elimination of
a
Reaction conditions: 1a (0.5 mmol), 2b−2o (1.0 mmol), PdCl2
(0.025 mmol) in DMSO (2.0 mL), 80 °C, 2 h, under a N2
b
atmosphere. Isolated yield.
the desired unsymmetrical disulfides. However, this can be
overcome through a different strategy (Scheme 4).
To further explore the scope and application of this catalytic
reaction, we tried the reactions (Scheme 4). This thiol−
disulfide exchange could be scaled up with comparable yield
(Scheme 4a). As mentioned above, the reaction of thiol 1a
with tert-butyl disulfides could not give the desired unsym-
metrical disulfide. Instead, tert-butyl thiol reacted with
symmetric aryl disulfides 2p and 2q, affording unsymmetrical
disulfides 4p and 4q, respectively, in excellent yields (Scheme
4b). Interestingly, the exchange of thiols with symmetric
diselenide and ditelluride afforded 5 and 6 in moderate to
good yields (Scheme 4c). Selenosulfides and tellurosulfides
have rarely been reported18 but have been attracting more
interest.22 The robustness of this approach was further
demonstrated by the late-stage functionalization of bioactive
scaffolds such as amino acids, peptides, and pharmaceuticals.
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Letter
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 5. Proposed Mechanism
AUTHOR INFORMATION
■
Corresponding Authors
Qitao Tan − Department of Chemistry, Innovative Drug
Research Center, Shanghai University, Shanghai 200444,
China; orcid.org/0000-0002-6220-651X;
Email: qttan@shu.edu.cn
Bin Xu − Department of Chemistry, Innovative Drug Research
Center, Shanghai University, Shanghai 200444, China; State
Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China; orcid.org/0000-0002-9251-
6930; Email: xubin@shu.edu.cn
Authors
complex A generates the palladium(0) species (B) and RSSR.
It is known that RSH 1 can be oxidized to RSSR by
DMSO.26,28 There are two possible pathways for the catalytic
reaction with Pd(0)L2 (B) as the catalyst. In pathway A,
oxidative addition of the starting symmetric disulfide R′SSR′
(2a) with Pd(0)L2 leads to intermediate C.26,29 Ligand
exchange of C with thiol 1 results in complex D, which gives
the desired unsymmetrical disulfide 3 and regenerates catalyst
B. In pathway B, oxidative addition of RSSR with Pd(0)L2
gives intermediate A, which reacts with complex C leading to
hybrid complex D presumably through complex E. Reductive
elimination of D also affords unsymmetrical disulfide 3. The
direct reaction of A with 2a through a similar intermediate
proposed by Tanaka and Ajiki is also possible.18b
In summary, we have disclosed a highly effective synthesis of
a broad range of unsymmetrical disulfides through thiol−
disulfide exchange under catalysis by the PdCl2/DMSO
system. This method features excellent functional group
tolerance, mild reaction conditions, and operational simplicity.
The robust nature of the reaction has been demonstrated by
the late-stage functionalization of biomolecules such as amino
acids, peptides, and pharmaceuticals without protecting the
free amino, hydroxyl, and carboxylic acid groups. Disulfide-
containing organic dyes such as pyrene and BODIPY
derivatives have also been prepared by this novel trans-
formation. Meanwhile, this transformation could be extended
to thiol−diselenide or thiol−ditelluride exchange, leading to
the synthesis of RSSeR′ or RSTeR′. Given the practical
reaction conditions and extensive applicability, we anticipate
that this operationally simple disulfuration protocol will find
widespread application in the modification of biomolecules,
pharmaceuticals, and materials.
Jimin Guo − Department of Chemistry, Innovative Drug
Research Center, Shanghai University, Shanghai 200444,
China
Jianjian Zha − Department of Chemistry, Innovative Drug
Research Center, Shanghai University, Shanghai 200444,
China
Tao Zhang − Department of Chemistry, Innovative Drug
Research Center, Shanghai University, Shanghai 200444,
China
Chang-Hua Ding − Department of Chemistry, Innovative
Drug Research Center, Shanghai University, Shanghai
200444, China; orcid.org/0000-0002-4628-4016
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00858
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation of
China (Grants 21971159 and 21871174) and the Innovation
Program of Shanghai Municipal Education Commission
(2019-01-07-00-09-E00008) for financial support. The authors
thank Prof. Bingxin Liu [Department of Chemistry, Shanghai
University (SHU)] for helpful discussions. The authors also
thank Prof. Hongmei Deng (Laboratory for Microstructures,
SHU) and Mr. Hui Wang (Department of Chemistry, SHU)
for spectroscopic measurements.
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ASSOCIATED CONTENT
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