Synthesis of heteroaryl containing sulfides via enaminone ligand assisted, copper-catalyzed C-S coupling reactions of heteroaryl thiols and aryl halides

Article abstract of DOI:10.1039/c4ra07187e

The C-S cross coupling reactions between electron deficient heteroaryl thiols and aryl halides have been smoothly performed to provide various heteroaryl containing sulfides in the presence of copper catalyst and enaminone ligand. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra07187e

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Synthesis of heteroaryl containing sulfides via
enaminone ligand assisted, copper-catalyzed C–S
Cite this: RSC Adv., 2014, 4, 37733
coupling reactions of heteroaryl thiols and aryl
halides†
Received 16th July 2014
Accepted 8th August 2014
a
Yunyun Liu, Bin Huang,a Xiaoji Cao,b Dan Wua and Jie-Ping Wana
*
DOI: 10.1039/c4ra07187e
www.rsc.org/advances
The C–S cross coupling reactions between electron deficient heter-
oaryl thiols and aryl halides have been smoothly performed to provide
various heteroaryl containing sulfides in the presence of copper
catalyst and enaminone ligand.
Introduction
Sulfur containing organic compounds prevalently present in the
ne chemicals, pharmaceuticals, materials, agrochemicals and
natural products.1–5 Therefore, the construction of C–S bonds is
an issue of considerable research interest in organic synthesis.
At present, transition metal-catalyzed coupling reactions of
thiols with aryl/vinyl halides are predominantly employed for
the synthesis of C–S bond containing organic molecules such as
thiols, suldes, S-containing heterocycles.6–9 Among the various
transition metal-catalyzed methods for C–S coupling reactions,
the copper-catalyzed version, also known as Ullmann C–S
coupling reaction, has been known as the most atom econom-
ical option. Numerous efforts have been devoted to establish
improved protocols on C–S coupling reactions between thiols
and aryl/vinyl halides based on copper catalysis, which leads to
signicant progress on the chemistry of C–S coupling reactions
by discovering new ligands, recyclable copper catalysts, renew-
able sulfur sources as well as reactions in green media.10–23
However, in contrast to the overwhelming reports on the
catalytic research of C–S coupling reaction, synthetic methods
towards product diversity, for example, the systematic synthesis
of heteroaryl containing suldes are still rare probably because
of the low nucleophilicity of most available heteroaryl thiols.24,25
In a previous study, we have disclosed that thiophenols 4 and
Scheme 1 Selective synthesis of different sulfides with different thiol
substrates.
(hetero)aryl halides 2 undergo tandem C–S cross coupling/C–H
functionalization to provide hydroxyl functionalized suldes 5 in
the presence of copper catalyst and an enaminone ligand
(Scheme 1).26 On the basis of this interesting transformation, we
have recently conducted extensive investigation on enaminone-
based ligand assisted Ullmann C-heteroatom and C–C coupling
reactions in order to expand the application scope of this kind of
ligands for the synthesis of structurally diverse organic prod-
ucts.27–30 Based on the structure of products 3, the C–H hydrox-
ylation may possibly happen in either the aryl backbone in the
thiophenols or the halides. While the examples using aryl and
heteroaryl halides both provide hydroxylated suldes 3 in the
previous work, however, the reactions using heteroaryl thiols 4
have not been examined. Therefore, in order to explore the
reaction more comprehensively and synthesize suldes with
higher diversity, we are inspired to investigate the coupling
reactions of heteroaryl thiols 4 with aryl halides 2. Herein, we
report the results from the systematic investigation on electron
decient thiol-based C–S coupling, which leads to selective
production of heteroaryl suldes 5 with broad application scope.
aKey Laboratory of Functional Small Organic Molecules, Ministry of Education, College
of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang
330022, P. R. China. E-mail: chemliuyunyun@gmail.com
bResearch Centre of Analysis and Measurement, Zhejiang University of Technology, 18
Results and discussion
Chaowang Rd, Hangzhou, Zhejiang 310014, P. R. China
† Electronic supplementary information (ESI) available: General experimental
information, full characterization data, 1H and 13C NMR spectra of all products.
See DOI: 10.1039/c4ra07187e
Initially, the coupling of 2-mercaptobenzothiazole 4a and
iodobenzene 2a was employed as a model reaction. In the
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presence of CuI catalyst and enaminone ligand L1 using found as the most favorable one (entries 11–14, Table 1).
DMSO as medium, the S-arylated product 5a was obtained as Further efforts in varying different solvents also gave just
the only product from the reaction, suggesting that a-hydrox- inferior yields of target product (entries 15–18, Table 1).
ylation in the sulde product only occurs when the substrates Finally, lowering the temperature led to sharp decrease in the
have a position available for this process. Based on the selec- yield of 5a (entry 19, Table 1).
tive production of heteroaryl sulde 5a, we consequently
With the optimized conditions in hand, we consequently
conducted optimization on this reaction. As shown in Table 1, turned to investigate the catalytic C–S coupling of different
the original screening of different copper catalysts, including aryl halides and a variety of heteroaryl thiols for the sake of
Cu(I) and Cu(II) catalysts, displayed that Cu(OAc)2 was the best establishing a generally applicable methodology. The results
copper catalyst (entries 1–5, Table 1). Subsequently, a class of in synthesizing heteroaryl suldes of diverse structures were
enaminone-based ligand L2–L4 and other frequently given in Table 2. According to these results, the present
employed ligand L-proline L5, 8-hydroxylquinoline L6 were protocol suited for the synthesis of heteroaryl suldes with
compared, which revealed that the enaminone-based ligand broad application scope via the employment of different
L3 was the best partner of the copper catalyst (entires 6–10, heteroaryl thiols such as 2-mercaptobenzothiazole (4a), 4,6-
Table 1). Following these results, different bases including dimethylpyrimidine-2-thiol (4b) and pyridinyl-2-thiol (4c) as
both organic and inorganic ones were then assayed. Among well as different aryl iodides and bromides. Generally, in the
these tested bases such as K2CO3, t-BuOK, DMAP, Cs2CO3 was reactions involving 4a, aryl iodides containing electron
withdrawing groups were better favored to give correspond-
ing products with moderate to excellent yield, while electron
enriched iodide such as p-methoxylphenyl iodide 2i under-
Table 1 Optimization on reaction conditionsa
went the C–S coupling to provide product 5i with low yield
(entry 9, Table 2). However, another electron enriched
substrate, the o-iodoaniline 2h coupled with 4a to give cor-
responding product 5h with much higher yield probably
because of the chelating effect of the amino group to copper
catalyst, which facilitated the catalysis of copper to the
desired coupling (entry 8, Table 2). Similar tendencies were
Entry Catalyst
Ligand Base
Solvent
T (ꢀC) Yieldb (%)
observed also in the reactions using heteroaryl thiols 4b and
4c as generally those aryl halides containing electron with-
drawing substituents were coupled successfully to afford
related suldes. Notably, some aryl bromides could also
participate the coupling reaction to yield disulde products
with moderate yields although the entry using bromo-
benzene gave only trace amount of expect transformation
(entries 13 and 14, Table 2). As reported previously, this
enaminone ligand assisted protocol was not applicable for
the synthesis of suldes using carbonaryl thiols containing
a-C–H bond because of the selective transformation of a-
hydroxylaiton.26
1
CuI
L1
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
100
100
100
100
100
100
100
100
100
100
100
100
100
100
60
83
80
70
80
79
95
81
72
83
16
53
80
71
20
2c
3
Cu(OAc)2 L1
CuSO4
Cu2O
CuBr
L1
L1
L1
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Cu(OAc)2 L2
Cu(OAc)2 L3
Cu(OAc)2 L4
Cu(OAc)2 L5
Cu(OAc)2 L6
Cu(OAc)2 L3
Cu(OAc)2 L3
Cu(OAc)2 L3
Cu(OAc)2 L3
Cu(OAc)2 L3
Cu(OAc)2 L3
Cu(OAc)2 L3
Cu(OAc)2 L3
Cu(OAc)2 L3
K2CO3
NaOH
DMAP
DMSO
DMSO
DMSO
t-BuOK DMSO
Cs2CO3 Toluene 100
Cs2CO3 EtOH
Cs2CO3 THF
Cs2CO3 Dioxane 100
Cs2CO3 DMSO 90
Reux 41
Reux 15
Conclusions
21
31
In summary, we have illustrated a copper-based catalytic
protocol for the C–S coupling reactions of electron decient
heteroaryl thiols with aryl halides. This work expands the scope
of known methods for the synthesis of these heteroaryl suldes,
the results are therefore useful as a complementary option in
the synthesis of heteroaryl suldes via simple starting
materials.
Acknowledgements
a
General conditions: 4a (0.5 mmol), 2a (0.6 mmol), copper catalyst (0.05
mmol), ligand (0.05 mmol) and base (1.0 mmol) in DMSO (2 mL), stirred
for 12 h. Yield of isolated product. All Cu(OAc)2 refers to the
commercially available reagent Cu(OAc)2$H2O.
The authors thank NSFC of China (no. 21202064) and a Spon-
sored Program for Cultivating Youths of Outstanding Ability in
Jiangxi Normal University (Y. Liu) for nancial support.
b
c
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Table 2 Synthesis of different heteroaryl sulfides via C–S coupling reactionsa
Entry
1
Thiol
Ar-X
Product
Yieldb (%)
Iodobenzene 2a
95
2
4a
1,4-Diiodobenzene 2b
42
3
4
4a
4a
p-Nitroiodobenzene 2c
p-Chloroiodobenzene 2d
51
93
5
6
7
8
4a
4a
4a
4a
o-Bromoiodobenzene 2e
1,3-Diiodobenzene 2f
1,2-Diiodobenzene 2g
o-Iodoaniline 2h
54
45
52
63
9
4a
p-Methoxyliodobenzene 2i
34
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Table 2 (Contd.)
Entry
10
Thiol
Ar-X
Product
Yieldb (%)
2a
94
11
12
13
4b
4b
4b
2c
42
29
33
2b
p-Bromoacetophenone 2j
14
4b
2,6-Dibromopyridine 2k
31
15
16
2a
2c
96
84
4c
17
18
19
4c
4c
4c
2b
2e
2d
57
36
49
20
4c
p-Tolyliodide 2l
45
a
General conditions: 4 (0.5 mmol), 2 (0.6 mmol), Cu(OAC)2$H2O (0.05 mmol), L3 (0.05 mmol) and Cs2CO3 (1.0 mmol) in DMSO (2 mL), stirred at
b
100 ꢀC for 12 h. Yield of isolated product.
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