8-hydroxyquinolin-N-oxide-promoted copper-catalyzed C-S cross-coupling of thiols with aryl iodides

Article abstract of DOI:10.1055/s-0032-1317518

8-Hydroxyquinolin-N-oxide was identified as a superior ligand for CuI-catalyzed C-S coupling reactions of aryl iodides with thiols to afford the corresponding thioethers in excellent yield. The method shows excellent chemoselectivity and high functional-group tolerance in both coupling partners. Copyright

Full text of DOI:10.1055/s-0032-1317518

LETTER
▌2853
letter
8-Hydroxyquinolin-N-oxide-Promoted Copper-Catalyzed C–S Cross-
Coupling of Thiols with Aryl Iodides
C–S Cross-Coupling of Thiols with Aryl Iodides
Kun Su,a,b Yatao Qiu,b Yiwu Yao,b Dayong Zhang,*a Sheng Jiang*b
a
Center of Drug Discovery, Chinese Pharmaceutical University, Nanjing 210009, P. R. of China
Fax +86(20)32015318; E-mail: zhangdayong@cpu.edu.cn
b
Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, CAS, Guangzhou 510663, P. R. of China
E-mail: jiang_sheng@gibh.ac.cn
Received: 27.08.2012; Accepted after revision: 10.10.2012
Abstract: 8-Hydroxyquinolin-N-oxide was identified as a superior
+
+
N
O–
OH
ligand for CuI-catalyzed C–S coupling reactions of aryl iodides
with thiols to afford the corresponding thioethers in excellent yield.
The method shows excellent chemoselectivity and high functional-
group tolerance in both coupling partners.
N
OH O–
L2
O
L1
Key words: C–S coupling reactions, copper, cross-coupling, 8-hy-
droxyquinolin-N-oxide, Ullmann reaction
OH
+
N
+
N
OH
O–
O
NH–
O
L4
L3
Transition-metal-catalyzed C–S bond formation is a very
important method in organic chemistry due to the impor-
tance of related compounds in biologically and pharma-
ceutically active molecules, as well as organic materials
and intermediates.1 During the development of this meth-
od, several transition metals such as palladium, copper,
nickel, cobalt, iron, and indium have been reported for this
purpose.2–7 Among them, the copper-catalyzed C–S cross-
coupling reactions have gained much more attention in the
past decades because copper is an inexpensive metal as
compared to palladium and other late-transition metals. It
is noteworthy that the ligand has played an important role
in improving both the efficiencies and scope of the meth-
odology. Recently, several classes of ligands, including
phosphazene,3a ethylene glycol,3b neocuproine,3c N-meth-
ylglycine,3d oxime–phosphine oxide ligand,3e tripod li-
gand,3f benzotriazole,3g 1,2-diaminocyclohexane,3h β-
ketoester,3i,j L-proline,3k BINAM,3l 1,2,3,4-tetrahydro-8-
hydroxyquinoline,3m and catechol violet,3n have been
found to accelerate copper-catalyzed C–S bond-forming
reactions.
Figure 1 Structures of previous reported ligands
tems comprised of the designed ligands. The prototypical
reaction conditions were 10 mol% of CuI, 20 mol% of the
ligand, and 1.5 equivalents of Cs2CO3 in DMSO (without
drying) at 80 °C (Table 1, entries 1–4). The results showed
that the highest yield (94%, Table 1, entry 2) was obtained
when L2 was employed as the ligand. The effect of sol-
vent was also evaluated, and DMSO is the most favorable
solvent for the catalytic reaction (Table 1, entries 2, 5, 6).
Using L2 as the ligand and DMSO as the solvent, reac-
tions employing other bases, including K2CO3, K3PO4,
and NaOt-Bu, were explored. NaOt-Bu was not suitable
as a base. Cs2CO3 performed as the best base. K2CO3 and
K3PO4 gave good results, but were not as good as Cs2CO3
(Table 1, entries 2, 10–12). The copper sources were also
found to have remarkable effects on the reaction. The re-
sults demonstrated that CuI was superior to the other cop-
per sources (Table 1, entries 2 and 7–9). No reaction was
observed without any copper source. The results of the
preliminary exploratory investigations described above
showed that the optimal conditions for the C–S coupling
reaction of 4-methyliodobenzene and thiophenol involves
the use of 10 mol% CuI, 20 mol% L1, and 2.0 equivalents
Cs2CO3 in DMSO at 80 °C.
Recently, we developed a series of new ligands which
could promote the copper-catalyzed C–N and C–O cou-
pling reaction under relatively mild conditions (Figure
1).8 Encouraged by this success, we envisioned that our
catalytic system might be used for the C–S coupling reac-
tion by choosing a suitable ligand. In this paper, we report
that 8-hydroxyquinolin-N-oxide (L2) serves as an effec-
tive ligand for the copper-catalyzed C–S bond-forming re-
actions.
The scope of the CuI–L1 catalytic process was carried out
under the optimized conditions, and the results are sum-
marized in Table 2.9 As shown in Table 2, both electron-
rich and electron-deficient aryl iodides were observed to
display similar reactivities. For example, reactions of aryl
iodides with a methyl substituent and thiophenol took
place in high yield (86–95%, Table 2, entries 1–3), while
the reaction of aryl iodides with a nitro substituent com-
pleted in 89–94% yield (Table 2, entries 6–8). It is notable
that the coupling proceeded well even with a sterically
4-Methyliodobenzene and thiophenol were selected as
model substrates to evaluate the catalytic activity of sys-
SYNLETT 2012, 23, 2853–2857
Advanced online publication: 13.11.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317518; Art ID: ST-2012-W0721-L
© Georg Thieme Verlag Stuttgart · New York

2854
K. Su et al.
LETTER
Table 1 Optimization of Conditions for the Copper-Catalyzed Coupling of p-Iodoanisole and Thiophenola
[CuX], ligand
base (2.0 equiv)
HS
S
I
+
Ar, solvent, 24 h
1a
2a
3a
Entry
Ligand
Base
Catalyst equivalent (mol%) Copper source
Solvent
Yield (%)b
1
2
L1
L2
L3
L4
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
30
10
0
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuBr2
CuAc
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
DMSO
DMSO
DMSO
DMSO
DMF
56
94
85
60
90
60
86
70
68
85
93
5
3
4
5
6
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
7
8
9
10
11
12c
13c
14c
15
16
17
18
K3PO4
NaOt-Bu
Cs2CO3
K2CO3
0
0
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
28
96
30
trace
L2
L2
L2
a Reaction conditions: 1a (1.5 mmol), 2a (1.0 mmol), [CuX] (10 mol%), ligand (20 mol%), base (2.0 mmol), solvent (1 mL), Ar, 80 °C, 24 h.
b Isolated yield.
c Conditions: r.t.
hindered substitute such as methyl and nitro at the ortho In summary, we have developed a simple, efficient, and
position (Table 2, entries 2, 3, 6, and 10). A heteroaryl io- general methodology for copper-catalyzed C–S coupling
dide (3-iodopyridine) also underwent coupling with an reactions of aryl iodides with thiols using inexpensive 8-
excellent yield of 92% (Table 2, entry 13). The coupling hydroxyquinolin-N-oxide as an ideal ligand. This method
reaction is also very chemoselective when a variety of shows excellent functional-group compatibility and high
other potentially reactive groups were present in the sub- selectivity in the presence of multiple potentially reactive
strate. For example, aryl iodides coupled with thiophenol groups at moderate temperatures.
without affecting chloro and bromo groups present in the
aryl ring (Table 2, entries 4, 5, 12, and 14). Moreover, the
reaction showed a high chemoselectivity to the thiols oth-
Acknowledgment
This research was supported by a grant from the National Natural
Science Foundation (Grant No. 30973607, 81172934, 20972160
and 21172220), the National Basic Research Program of China
(Grant No. 2009CB940900), and CSA-Guangdong Joint Foundati-
on (Grant No. 2011B090300069) for their financial support.
er than arylation on the amino group (Table 2, entry 11).
Finally, we observed that the coupling of 1-iodo-4-meth-
ylbenzene with various thiols such as 2-bromo-, 2-methyl-
, 4-methyl-, 4-methoxy-, 2-amino-, and 4-aminobenzene-
thiol underwent the reaction in 90–98% yield (Table 2, en-
tries 15–20).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Synlett 2012, 23, 2853–2857
© Georg Thieme Verlag Stuttgart · New York

LETTER
C–S Cross-Coupling of Thiols with Aryl Iodides
2855
Table 2 CuI-Catalyzed C–S Coupling Reaction of Aryl Iodides with Thiolsa
CuI (10 mol%)
L2 (20 mol%)
S
R2
+
R2
R1
I
HS
R1
Cs2CO3 (2.0 equiv)
DMSO, 80 °C
Entry
Aryl iodide
Thiol
Product
Yield (%)b
92
I
HS
S
1
2
1a
3a
2a
I
HS
S
95
86
3b
1b
1c
2a
HS
S
I
3
4
2a
3c
I
S
HS
90
Cl
Cl
2a
1d
3d
I
S
HS
5
6
91
94
Cl
Cl
2a
1e
3e
I
S
HS
NO2
NO2
2a
1f
3f
S
I
HS
7
8
89
95
90
92
NO2
NO2
2a
1g
3g
S
I
HS
O2N
O2N
2a
1h
3h
I
S
HS
MeO
MeO
O
9
O
2a
1i
3i
I
S
HS
10
NO2
NO2
2a
1j
3j
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2853–2857

2856
K. Su et al.
LETTER
Table 2 CuI-Catalyzed C–S Coupling Reaction of Aryl Iodides with Thiolsa (continued)
CuI (10 mol%)
S
R2
L2 (20 mol%)
+
R2
R1
I
HS
R1
Cs2CO3 (2.0 equiv)
DMSO, 80 °C
Entry
Aryl iodide
Thiol
Product
Yield (%)b
I
S
HS
11
88
NH2
NH2
2a
1k
3k
I
S
HS
12
13
14
15
96
92
88
93
Br
Br
2a
1l
3l
I
S
HS
N
N
2a
1m
3m
I
S
HS
Cl
Br
Cl
Br
2a
1n
3n
HS
S
I
Br
Br
1a
1a
1a
1a
2b
3o
3p
3q
S
I
I
I
HS
16
17
18
96
98
95
2c
HS
S
S
2d
HS
OMe
OMe
NH2
2e
3r
3s
3t
HS
S
I
I
19
20
90
92
NH2
1a
2f
S
HS
H2N
H2N
1a
2g
a Reaction conditions: ArI (1.5 mmol), thiol (1.0 mmol), Cs2CO3 (2.0 mmol) CuI (0.10 mmol, 10 mol%), L5 (0.20 mmol, 20 mol%), DMSO
(1.0 mL), 80 °C, argon.
b Isolated yield.
(b) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev.
References and Notes
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Synlett 2012, 23, 2853–2857
© Georg Thieme Verlag Stuttgart · New York

LETTER
Johanson, A.; Nikiforovich, G. V.; Gogoll, A.; Synnergren,
C–S Cross-Coupling of Thiols with Aryl Iodides
2857
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(2) For recent contributions on Pd-catalyzed C–S coupling
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Jiang, S. Org. Biomol. Chem. 2011, 9, 8224.
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(9) General Experimental Procedure
An argon-filled flask was charged with CuI (20 mg, 0.1
mmol, 10 mol%), L5 (32 mg, 0.2 mmol, 20 mol%), Cs2CO3
(652 mg, 2 mmol, and thiophenol (1 mmol). The aryl iodide
(1.5 mmol) and DMSO (1 mL) were injected into the flask
under argon atmosphere. The contents were then stirred at 80
°C for 24 h. After allowing the mixture to cool to r.t., the
mixture was diluted with EtOAc (20 mL) and filtered. The
filtrate was washed with H2O (2 × 10 mL). The organic
phase was dried with Na2SO4, filtered, and the solvent was
removed under vacuum, and the residue was purified by
chromatography on silica gel to give the desired aryl sulfide.
Spectroscopic Data of the Representative Compounds:
(2,4,6-Trimethylphenyl)phenyl Sulfide (3c)
1HNMR (400 MHz, CDCl3): δ = 7.19–7.15 (t, J = 7.60 Hz, 2
H), 7.07–7.01 (m, 3 H), 6.93–6.91 (d, J = 7.60 Hz, 2 H), 2.39
(s, 6 H), 2.32 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ =
143.7, 139.2, 138.4, 129.3, 128.8, 126.9, 125.5, 124.4, 21.7,
21.1.
(4) For recent contributions on Ni-catalyzed C–S coupling
reactions, see: (a) Zhang, Y.; Ngeow, K. N.; Ying, J. Y. Org.
Lett. 2007, 9, 3495. (b) Jammi, S.; Barua, P.; Rout, L.; Saha,
P.; Punniyamurthy, T. Tetrahedron Lett. 2008, 49, 1484.
(5) For recent contributions on Co-catalyzed C–S coupling
reactions, see: Wong, Y. C.; Jayanth, T. T.; Cheng, C. H.
Org. Lett. 2006, 8, 5613.
(6) For recent contributions on Fe-catalyzed C–S coupling
reactions, see: (a) Correa, A.; Carril, M.; Bolm, C. Angew.
Chem. Int. Ed. 2008, 47, 2880. (b) Wu, W. Y.; Wang, J. C.;
Tsai, F. Y. Green. Chem. 2009, 11, 326.
3-Pyridyl Phenyl Sulfide (3m)
1HNMR (400 MHz, CDCl3): δ = 8.56–8.55 (s, 1 H), 8.46–
8.45 (q, J = 4.8 Hz, 1 H), 7.60–7.58 (d, J = 8.00 Hz, 1 H),
7.39–7.29 (m, 5 H), 7.22–7.19 (q, J = 4.80 Hz, 1 H). 13
NMR (125 MHz, CDCl3): δ = 151.1, 147.8, 137.9, 133.9,
133.6, 131.7, 129.5, 127.8, 123.9.
C
2-(4-Tolylsulfanyl)phenyl Bromide (3o)
1HNMR (400 MHz, CDCl3): δ = 7.54–7.52 (d, J = 7.6 Hz, 1
H), 7.40–7.38 (d, J = 8.00 Hz, 2 H), 7.23–7.21 (d, J = 8.00
Hz, 1 H), 7.13–7.08 (m, 1 H), 7.00–6.96 (m, 1 H), 6.82–6.79
(dd, J = 7.60 Hz, 1 H), 2.38 (s, 3 H). 13C NMR (125 MHz,
CDCl3): δ = 139.8, 139.0, 134.4, 132.9, 130.5, 128.7, 128.7,
127.7, 126.6, 122.0, 21.3.
(7) For recent contributions on In-catalyzed C–S coupling
reactions, see: (a) Reddy, V. P.; Swapna, K.; Kumar, A. V.;
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2853–2857

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