Cu-Catalyzed Electrophilic Disulfur Transfer: Synthesis of Unsymmetrical Disulfides

Article abstract of DOI:10.1021/acs.orglett.8b01418

An efficient electrophilic persulfuration reaction leading to unsymmetrical disulfides and polysulfides has been developed. Various nucleophiles, including aryl boronic acids, β-keto esters, and thiols, can be used as substrates. The notable features of t

Full text of DOI:10.1021/acs.orglett.8b01418

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Cu-Catalyzed Electrophilic Disulfur Transfer: Synthesis of
Unsymmetrical Disulfides
Weiguo Wang,† Yunzhi Lin,† Yudao Ma,† Chen-Ho Tung,† and Zhenghu Xu*,†,‡
†Key Lab for Colloid and Interface Chemistry of Education Ministry, School of Chemistry and Chemical Engineering, Shandong
University, Jinan 250100, P. R. China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
S
* Supporting Information
ABSTRACT: An efficient electrophilic persulfuration reac-
tion leading to unsymmetrical disulfides and polysulfides has
been developed. Various nucleophiles, including aryl boronic
acids, β-keto esters, and thiols, can be used as substrates. The
notable features of this method include very simple and
practical conditions, general scope, and inexpensive copper
catalysts.
olecules containing sulfur−sulfur bonds (S−S), includ-
ing disulfides and polysulfides, have attracted significant
between two cysteine residues is an excellent method with
which to stabilize the secondary structure of a protein and
enhance its pharmacological properties.1b Many well-known
commercial peptide drugs such as insulin, lantus, vasopressin,
and plecanatide contain one or more disulfide bonds. In
addition, by taking advantage of the unstable nature of the
disulfide bond, it has been used in drug discovery and delivery
as a readily cleavable linkage.3a Consequently, the development
of efficient synthetic methods to produce disulfides and
polysulfides is important.6,7
M
attention because of their unique structural, chemical, and
biological properties1 and their wide use in food chemistry2
and in the pharmaceutical industry.3 This structural unit is
present in garlic and other allium compounds, such as garlicin
(I), which are used in food flavoring and also as traditional
medicines (Scheme 1). Recently, abundant disulfide- and
Scheme 1. Representative Natural Products and
Pharmaceuticals Containing Disulfides and Polysulfides
Symmetrical disulfides can be easily formed by oxidative
coupling of thiols, but synthesis of asymmetric disulfides in this
way is complicated by the byproducts inevitably formed by
homocoupling.6a,d Retrosynthetic analysis suggests two possi-
ble pathways to asymmetric disulfides: S−S bond formation
and C−S bond formation (Scheme 2A). The currently used
synthetic methods depend on S−S bond formation in the
reaction between a thiol substrate and electrophilic sulfenyla-
tion reagent such as RSSO2Me and require multiple steps to
prepare malodorous thiols and the sulfenylation reagent in
advance.6a A more straightforward approach is a persulfur
group transfer reaction through C−S bond formation, which
could introduce “SSR” moieties directly into an organic
molecule in one step. However, this is challenging because
preserving the fragile S−S bond intact is difficult in such
reactions. Only two examples of a persulfur group transfer have
been reported and both used a nucleophilic disulfur reagent. In
2016, Xian’s group reported a nucleophilic reaction of 9-
fluorenymethyl disulfides7 and Jiang et al. developed an elegant
polysulfide-containing natural products isolated from marine
organisms have been shown to exhibit important biological
activities, and many of them have been used as lead and
candidate drugs.4 The disulfide or polysulfide moieties play
important roles in their bioactivities. For instance, varacin (II),
a dopamine alkaloid, exhibits potent antifungal and antitumor
activity,5,5a and aranotin (III) has significant antiviral proper-
ties.5b In peptide therapeutics, disulfide bond formation
Received: May 4, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01418
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Synthetic Strategies for Unsymmetrical
Table 1. Optimization of Reaction Conditions
Disulfides
b
entry
catalyst
base
temp (°C)
yield of 2a (%)
1
2
3
4
5
6
7
8
9
CuSO4
Cu(OAc)2
CuI
CuSO4
Cu(OAc)2
Cu(OTf)2
CuCl2
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
CsF
25
25
25
60
60
60
60
60
60
60
60
37 (2a:2a′ = 4:1)
31 (2a:2a′ = 3:1)
25 (2a:2a′ = 3:1)
83
58
32
38
17
CuI
CuSO4
CuSO4
CuSO4
61
trace
57
10
11
Cs2CO3
NaHCO3
c
a
Reaction conditions: 1 (0.2 mmol), phenylboronic acid (0.4 mmol),
catalyst (20 mol %), base (0.4 mmol), and MeOH (1 mL) were
b
stirred at 60 °C under N2 atmosphere for 12 h. Isolated yield.
c
Catalyst (10 mol %).
screened, but it was found that at room temperature large
amounts of undesired desulfuration products such as TsStBu
and ArStBu and deboration products were formed (Table 1,
entries 1−3). After detailed examination of different reaction
conditions, we found that upon raising the reaction temper-
ature to 60 °C and increasing the transmetalation rate the
expected reaction proceeded well in the presence of a catalytic
amount of CuSO4. The desired disulfide (2a) was isolated in
83% yield, and formation of the desulfuration and deboration
side products was largely inhibited (entry 4). Other copper
catalysts such as Cu(OAc)2, Cu(OTf)2, CuCl2, and CuI are all
less effective than CuSO4 (entries 5−8). Variation of other
bases (entries 9 and 10) and trying to lower catalyst loadings
(entry 11) all led to a lower reaction yield.
The scope of various commercial available aryl boronic acids
was investigated, and a series of unsymmetrical disulfides were
synthesized in good to excellent yields under the standard
conditions (Scheme 3). Different electron-donating or
electron-withdrawing functional groups at the ortho, meta, or
para positions do not affect this reaction and give products
2b−k in good yields. A series of functional groups such as
bromo, cyano, ester, acetyl, and methylthio were well tolerated
under these reaction conditions, thus allowing further
functionalization if necessary. Various hydrocarbons such as
naphthalene- and anthracene-derived boronic acids were also
suitable for this transformation, giving the corresponding
disulfides in 81% and 77% yields (2l,m).Various heterocycles
such as pyridine (2n,o), quinoline (2p), and benzothiophene
(2q) are all compatible with the reaction. Styrylboronic acid
reacts efficiently to produce the target disulfide (2r) in 89%
yield, and p-phenyldiboronic acid reacts smoothly, giving the
persulfide (2s) in moderate yield.
copper-catalyzed disulfuration reaction that can be used in
oxidative coupling reactions8 (Scheme 2B). However, this
oxidative coupling reaction requires extra oxidants and
complex reaction conditions and we reasoned that direct
electrophilic disulfuration of various nucleophiles (Scheme
2C) is a simpler and more practical approach. In this paper, we
report our preliminary results.
Benzenesulfonothioate is an effective electrophilic sulfenylat-
ing reagent as a result of the leaving properties of
benzenesulphinate, with the pKa of corresponding acid being
2.76.9 Previously, we have used this reagent to trap
arylcopper(I) intermediates and form C−S bonds.9a The
Shen group has also developed PhSO2SCF2H as an efficient
electrophilic difluoromethylthiolation reagent.10 We sought to
apply this strategy in electrophilic disulfuration reactions using
SS-tert-butyl p-toluenesulfono(dithioperoxoate) (1), which
could be prepared easily from potassium p-toluenesulfono-
thioate with tert-butyl thiochloride.11 There are two weak S−S
bonds in this reagent (1), and how to cleave one S−S bond
over another is a challenge. We reasoned that the good leaving
tendency of the arylsulfone moiety may help cleave the
thioester bond rather than the persulfur bond, realizing the
desired persulfur transfer reaction. Recently, we have
successfully applied this reagent in an efficient copper(I)-
catalyzed three-component click/persulfuration cascade reac-
tion for the synthesis of triazole disulfides.12
The viability of electrophilic persulfuration with different
nucleophiles was explored. The reactivity of aryl boronic acid, a
commercially available, easily prepared, and widely used
arylation reagent, was evaluated. We reasoned that a copper
reagent maybe a suitable catalyst to promote this reaction
through boron to copper transmetalation,9d,10b generating aryl
copper intermediate M1, followed by an electrophilic
persulfuration reaction, which could form the target product.
This step might go through an oxidative addition and reductive
elimination sequence (Table 1). Various copper catalysts were
We then began to extend this electrophilic persulfuration
reaction to other nucleophiles. Various β-keto esters were
explored and these Csp3-S bond formation reactions were very
successful (Scheme 4). Indanone- and tetralone-derived β-keto
esters were subjected to this reaction in the presence of DMAP
as a base; the target asymmetric disulfides 3a and 3b were
B
DOI: 10.1021/acs.orglett.8b01418
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
generate a trisulfide in a single step, and indeed, reactions of
various thiols with 1 occur efficiently at room temperature
without any catalyst or base, and the corresponding trisulfides
4a−c can be isolated in excellent yields (Scheme 4). The
reaction of an aliphatic thiol, benzyl mercaptan, gave the
trisulfide (4d) in 50% yield. Such trisulfide products are
difficult to synthesize by other methods.
Scheme 3. Electrophilic Persulfuration of Aryl Boronic
Acids
a
In summary, we have developed an efficient electrophilic
persulfuration reaction which constructs unsymmetrical
disulfides and trisulfides by introducing two sulfur atoms in
one step. Various nucleophiles, including aryl boronic acids
and thiols, are all compatible substrates in this general
electrophilic persulfur-transfer reaction. Notable features of
this method include very simple and mild reaction conditions,
inexpensive copper catalysts, and a very broad substrate scope.
Further application of this methodology is in progress in our
laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01418.
Experimental details and spectral data for new
compounds (PDF)
a
Reaction conditions: aryl or vinyl boronic acid (0.4 mmol), reagent 1
(0.2 mmol), CuSO4 (20 mol %), and NaHCO3 (0.4 mmol) in MeOH
(1 mL) were stirred at 60 °C for 12 h. Isolated yields are reported.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xuzh@sdu.edu.cn.
ORCID
Scheme 4. Substrate Scope of Thiols and Ketoesters
Chen-Ho Tung: 0000-0001-9999-9755
Zhenghu Xu: 0000-0002-3189-0777
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the Natural Science
Foundation of China and Shandong Province (Nos. 21572118
and JQ201505) and for the Tang Scholar Award of Shandong
University.
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