Direct cross-coupling access to diverse aromatic sulfide: Palladium-catalyzed double C-S bond construction using Na2S 2O3 as a sulfurating reagent

Article abstract of DOI:10.1021/ol500112y

The Pd-catalyzed cross-coupling of aryl halides, alkyl halides, and Na ₂S₂O₃·5H₂O to deliver aromatic thioethers is described. Pyridine, furan, thiophene, benzofuran, benzoxazole, benzothiophene, benzothiazole, and pyrazine are all amenable to this protocol. The odorless and stable solid Na₂S₂O ₃·5H₂O was used as a convenient and environmentally friendly source of sulfur. Pd-catalyzed cross-couplings without thiols or thiophenols to build C-S bonds have not previously been achieved, which renders our observation more striking.

Full text of DOI:10.1021/ol500112y

Letter
pubs.acs.org/OrgLett
Direct Cross-Coupling Access to Diverse Aromatic Sulfide: Palladium-
Catalyzed Double C−S Bond Construction Using Na2S2O3 as a
Sulfurating Reagent
Zongjun Qiao,† Jianpeng Wei,† and Xuefeng Jiang*,†,‡
†Shanghai Key Laboratory of Green Chemistry and Chemical Process, Department of Chemistry, East China Normal University,
3663 North Zhonshan Road, Shanghai 200062, P. R. China
‡State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. China
S
* Supporting Information
ABSTRACT: The Pd-catalyzed cross-coupling of aryl halides, alkyl halides, and Na2S2O3·5H2O to deliver aromatic thioethers is
described. Pyridine, furan, thiophene, benzofuran, benzoxazole, benzothiophene, benzothiazole, and pyrazine are all amenable to
this protocol. The odorless and stable solid Na2S2O3·5H2O was used as a convenient and environmentally friendly source of
sulfur. Pd-catalyzed cross-couplings without thiols or thiophenols to build C−S bonds have not previously been achieved, which
renders our observation more striking.
Scheme 1. Strategies for Cross Coupling
rganosulfur chemistry has gained attention because
Osulfur-containing building blocks serve important func-
tions in general organic synthesis1 as well as applications in the
pharmaceutical industry,2 material science,3 and food chem-
istry.4 Because of the significance of organosulfur compounds,
the development of new, efficient, and environmentally benign
synthetic methodologies for the incorporation of sulfur into
organic frameworks is an important and challenging task.5 Pd-
catalyzed cross-coupling reactions have been developed into
classical transformations for the construction of C−O and C−
N bonds.6 However, Pd-catalyzed C−S bond formation has
been less studied due to the deactivation of the metal catalysts
by strong coordinating properties.7 Migita’s group realized the
first Pd-catalyzed Csp2−S bond formation in 1980.8 More
recently, contributions by Hartwig,9a−c Lee,9d Kim,9e Stambu-
li,9f and Zheng9g,h have appeared in Pd-catalyzed cross-coupling
with the help of special additives (ligands, indium, or zinc) for
protecting palladium from sulfur poisoning. Other transition
metals, such as Cu,10 Ni,11 Co,12 Fe,13 Au,14 Rh,15 and Pt,16
have emerged as appealing catalysts for this reaction.
To overcome these problems, the key point is to look for
different thiol surrogates as independent sulfur sources to
realize a free combination of the two coupling partners (Csp2−
X and Csp3−X halides) without thiol (Csp2−SH) or
thiophenol (Csp3−SH). Very recently, our group has described
Pd-catalyzed intramolecular double C−S bond formation by
using Na2S2O3·5H2O.17 We envisioned that the structural
feature of thiosulfate anion could repress the notorious
sensitivity of sulfur for late-transition-metal catalysts. In
addition, we used Na2S2O3·5H2O as the sulfur source instead
Generally, organometallic transformation methodologies for
C−S bond formation involve thiophenol coupling with halide.
The other method for C−S bond formation employs thiol as a
coupling partner (Scheme 1, entries a and b). According to
these two strategies, thiols or thiophenols function as sulfur
sources, which are indispensable partners. However, the
method generally suffers from preparation difficulties, unpleas-
ent smell, easy oxidation, and toxicity during the entire process.
Received: January 13, 2014
Published: February 6, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Table 2. Synthesis of Substituted Phenyl Sulfidesa,b
of prepared sulfide, a one-pot reaction, to avoid a series of
problems in the process of raw material preparation. Base on
this hypothesis and our previous work, we are eager to develop
a new catalytic system to improve the practicality of aryl sulfide
generation in cross-coupling reactions.
We commenced our study by investigating the cross-
coupling of 4-iodoacetophenone and 1-chlorobutane under
our aforementioned strategy. We were pleased to find that the
desired product was isolated in 45% yield under PdCl2(dppf)
catalyst in a sealed tube (Table 1, entry 1). Different palladium
a
Table 1. Optimization of the Reaction Conditions
b
[Pd]
(10 mol %)
ligand
(mol %)
base
(3 equiv)
yield
(%)
entry
solvent
c
1
PdCI2(dppf)
dppf (5)
dppf (5)
Cs2CO3
Cs2CO3
Cs2CO3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
45
c
2
NR
35
substituted functional groups but also polysubstituted com-
pounds (Table 2, 2k and 2l) and anthracene structures (Table
2, 2m).
c
3
PdCI2(dppf)
PdCI2(dppf)
PdCI2(dppf)
PdCI2(dppf)
PdCI2(dppf)
Pd(dba)2
c
4
dppf (5)
dppe (5)
dppp (5)
dppb (5)
dppp (15)
dppf (5)
dppf (5)
dppf (5)
dppf (5)
dppf (5)
dppf (5)
dppf (5)
dppf (5)
dppf (5)
dppf (5)
dppf (15)
NR
31
c
5
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DBU
Considering the significance of heteroarenes in drug
molecules, we were eager to test whether or not this protocol
is compatible with heterocyclic substrates. Remarkably, various
heterocyclic halides could be converted to the corresponding
product in good to excellent yields (Table 3). Furan with free
aldehyde exhibited very good tolerance with different halides
(Table 3, 3b). Hydroxyl-containing halide is of compatibility in
this reaction (Table 3, 3al). It is worth noting that secondary
c
6
46
c
7
29
c
8
trace
46
9
PdCI2(dppf)
PdCI2(dppf)
PdCI2(dppf)
PdCI2(dppf)
PdCI2(dppf)
PdCI2(dppf)
PdCI2(dppf)
PdCI2(dppf)
PdCI2(dppf)
PdCI2(dppf)
PdCI2(dppf)
10
11
12
13
14
15
16
17
18
19
DMSO
CH3NO2
NMP
47
NR
NR
d
DMF
57
d
a b
,
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
63
Table 3. Synthesis of Substituted Heterocyclic Sulfides
d
ND
d
NaOAc
K3PO4
ND
d
ND
e
Cs2CO3
Cs2CO3
40
f
88
a
Reaction conditions: Ar-I (0.2 mmol), n-Bu-Cl (3.0 mmol), [Pd]
(0.02 mmol), ligand (0.01 mmol), base (0.6 mmol), Na2S2O3·5H2O
b
(1.0 mmol), solvent (4.0 mL), 120 °C, Schlenk tube, 10 h. Isolated
c
d
e
yield. H2O (0.2 mL), 150 °C, sealed tube. Glycol (0.2 mL). Glycol
f
(0.4 mL). Glycol (0.1 mL).
catalysts and ligands were screened, which showed that
PdCl2(dppf) with dppf is a better choice (Table 1, entries 5−
8). The system was much cleaner when DMSO was used as a
solvent in a Schlenk tube and the temperature was lowered to
120 °C (Table 1, entry 10). When glycol was added as a
cosolvent in DMSO, the yield was increased to 63% (Table 1,
entry 14). The base played an important role in the
transformation. No product was detected when DBU,
NaOAc, and K3PO4 were used instead of Cs2CO3 (Table 1,
entries 15−17). To our delight, when the ratio of DMSO to
glycol was changed to 40:1, the yield was elevated to 88%
(Table 1, entry 19).
Having identified the optimal conditions, the substrate scope
of this reaction was investigated. As shown in Table 2, the aryl
iodides bearing different electron-withdrawing groups, such as
formyl (Table 2, 2a), nitryl (Table 2, 2g, 2h, and 2i), and cyano
group (Table 2, 2d, 2e, and 2f) substituted at the ortho-, para-,
or meta-position, could proceed smoothly. However, target
products could not be obtained in electron-rich aromatic
systems. The method is compatible with not only single
a
Reaction conditions: Ar-X (0.2 mmol), alkyl-Cl (3.0 mmol),
PdCl2(dppf) (0.02 mmol), dppf (0.01 mmol), Cs2CO3 (0.6 mmol),
Na2S2O3·5H2O (1.0 mmol), DMSO (4.0 mL), glycol (0.1 mL), 120
b
c
°C. Isolated yield. Alkyl-Cl (1.0 mmol).
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Organic Letters
Letter
a
halides, such as cyclopentane, cycloheptane, and cyclooctane,
showed great reactivity as well (Table 3, 3bf, 3bg, and 3bh).
Pyridine was also an efficient coupling partner with various
halides (Table 3, 3a). Dibromopyridine could give product 3db
in 44% yield with cross coupling twice. Pyrazine, benzofuran,
benzothiophene, benzoxazole, and benzothiazoleare were all
amenable to the reaction, which provided the possibilities for
drug late-stage modification.
Scheme 3. Modification of Drugs and Complex Substrates
To test the reaction’s practical utility, a gram-scale reaction
was carried out by using 2-bromopyridine and 1-chlorooctane,
which affords the desired product 1.19 g (Scheme 2, I).
a
Scheme 2. Further Exploration
a
Reaction conditions: Ar-X (0.1 mmol), X = I, Br or Cl, alkyl-Cl (15.0
mmol), PdCl2(dppf) (0.01 mmol), dppf (0.005 mmol), Cs2CO3 (0.3
mmol), Na2S2O3·5H2O (0.5 mmol), DMSO (2.0 mL); glycol (0.05
mL), 120 °C.
Scheme 4. Proposed Mechanistic Cycle
a
Reaction conditions: 2-bromopyridine (7.0 mmol, 1.0 equiv), 1-
chlorooctane (56.0 mmol, 8.0 equiv), PdCl2(dppf) (0.35 mmol, 5.0
mol %), dppf (0.18 mmol, 2.5 mol %), Cs2CO3 (1.5 mmol, 2.1 equiv),
Na2S2O3·5H2O (25.0 mmol, 3.6 equiv), DMSO (40.0 mL), glycol (1
mL), 120 °C.
Different prepared thiosulfate salts were viable substrates for
this transformation when water was added to the system
(Scheme 2, II). Further explorations of the application of this
strategy by using an independent sulfur source have shown
practicability, variability, and ease of operation. In addition, it is
known that late-stage modification of drug candidates is
valuable for structure−activity relationship studies. Various
complex derivatives of pharmaceutical importance were
examined to prove the synthetic potential of this strategy. We
were pleased to find that derivatives of sulfamethoxazole,
metronidazole, and amino acid (Scheme 3), biological active
molecules with different kinds of heteroatoms, were all tolerant
in this transformation. The structure of 5b was confirmed by X-
ray analysis.18
Although a precise reaction mechanism remains to be
established, a plausible mechanism is outlined (Scheme 4). We
assumed that palladium intermediate 3 could be generated via
the oxidative addition of Pd(0) 1. Csp3−Cl reacted with
thiosulfate to form thiosulfate-substituted organic salt 5.
Subsequent ligand exchange between intermediate 3 and 5
produced palladium thiosulfate 6, which could transform to 7
via the release of SO3. In that process, the electron-withdrawing
effect of the sulfonic acid group weakened the strong
coordinating properties of sulfur to palladium. Meanwhile,
reductive elimination of Pd(II) was accelerated by sulfur
trioxide leaving from the intermediate 7. Then intermediate 7
gave the product thioether 8 and regenerated Pd(0).
In conclusion, we have developed a novel method for diverse
aromatic sulfide by Pd-catalyzed cross coupling. The important
feature of this method is using the odorless, stable, and
environmentally friendly Na2S2O3·5H2O salt as a sulfurating
reagent which is commercially available and easily handled.
This method provides a free cross-coupling approach to
aromatic sulfide, which is an important unit in biologically
active molecules. Various pharmaceutical molecules were
examined to prove the synthetic potential of this strategy.
Further studies to deeply understand the reaction mechanism
and synthetic applications are ongoing in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Procedure, NMR spectra, X-ray data, and analytical data for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xfjiang@chem.ecnu.edu.cn.
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Organic Letters
Letter
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by NSFC (21272075), NCET
(120178), DFMEC (20130076110023), the “Shanghai Pujiang
Program” (12PJ1402500), the program for Professor of Special
Appointment (Eastern Scholar) at Shanghai Institutions of
Higher Learning, and the program for Changjiang Scholar and
Innovative Research Team in University.
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(18) CCDC-980603 (5b): C12H11F3N4O2S, MW = 332.31,
monoclinic, space group P2(1)/c, final R indices [I > 2σ(I)], R1 =
0.0661, wR2 = 0.1910, R indices (all data), R1 = 0.0750, wR2 =
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reflections collected/unique: 15637/2440 (R(int) = 0.0250). These
data can be obtained free of charge from the Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/ci
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