Copper-catalyzed coupling of thiourea with aryl iodides: The direct synthesis of aryl thiols

Article abstract of DOI:10.1002/cjoc.201090246

A general, economical and efficient protocol for the direct copper-catalyzed coupling of thiourea with aryl iodides is developed and it will be potentially applied in large-scale industry as a preferred process.

Full text of DOI:10.1002/cjoc.201090246

FULL PAPER
Copper-Catalyzed Coupling of Thiourea with Aryl Iodides:
The Direct Synthesis of Aryl Thiols
Qiao, Shu(乔澍)
Xie, Kun(谢昆)
Qi, Junsheng*(祁俊生)
College of Chemical and Environmental Engineering, Chongqing Three Gorges University, Wanzhou, Chongqing
404000, China
A general, economical and efficient protocol for the direct copper-catalyzed coupling of thiourea with aryl io-
dides is developed and it will be potentially applied in large-scale industry as a preferred process.
Keywords metalation, synthesis methods, aryl iodide, coupling reaction, aryl thiols
Introduction
marized in Table 1. Only a few amount of the expected
products were formed without the Cu salt (Table 1, En-
tries 1 and 2). However, the product was obtained in
77% yield when CuCl and L-proline were used respec-
Organosulfur compounds are integral part of nu-
merous pharmaceuticals, polymers, and natural prod-
ucts.1 Traditional methods for constructing aryl-sulfur
bonds include thermal rearrangement of N,N-dialkyl-
thiocarbamates or substitution via an addition-elimina-
tion mechanism.2 However, these reactions often require
harsh conditions, such as high temperature, long reac-
tion times and low yields. Since 1980, the development
of transition metal-catalyzed coupling has acquired a
great advancement. On the other hand, modern transi-
tion-metal-catalyzed coupling reactions (palladium,3
nickel,4 copper,5 cobalt,6 iron7 and indium8) have been
developed as an efficient method for aryl-sulfur bond
formation, using alkyl thiol as a sulfur source. The de-
sired aryl thiols are obtained after cleavage of the alkyl-
sulfur bond, which typically requires harsh conditions.
Thiourea is one of the basic feedstocks of chemistry,
and its low cost and wide availability make it an ex-
tremely attractive source of sulfur for synthetic chemis-
try. The use of thiourea as a coupling partner in transi-
tion metal-catalyzed S-aryl reactions would allow the
direct synthesis of valuable aryl thiols from simple aryl
iodides. However, catalytic reactions utilizing thiourea
are extremely rare.9 Most protocols employing palla-
dium or nickel as catalyst suffer from several drawbacks,
e.g. toxic, expensive ligands.
Table 1 Optimization of reaction conditiona
Entry [Cu]
Ligand
—
Base
Solvent Yieldb/%
1
2
—
NaOBu-t
NaOBu-t
NaOBu-t
NaOBu-t
NaOBu-t
NaOBu-t
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
13
12
77
80
98
76
45
57
32
23
86
58
42
69
48
42
35
—
L-Proline
3
CuCl L-Proline
CuBr L-Proline
4
5
CuI
L-Proline
6
Cu2O L-Proline
7
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
1,10-Phen NaOBu-t
8
DMEDA
TMEDA
TMHD
NaOBu-t
NaOBu-t
NaOBu-t
NaOBu-t
9
10
11
12
13
14
15
16
17
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
NaOBu-t Toluene
NaOBu-t Dioxane
Herein, we first develop the arylation of thiourea
catalyzed by simple and cheap copper source. Sulfura-
tion of both activated and inactivated aryl and heteroaryl
iodides can be achieved under mild conditions in this
catalytic system in which the less toxic and inexpensive
coppers is used together with simple amino acid ligands.
Initially, a set of experiments were carried out using
iodobenzene and thiourea as model substrates for opti-
mizing the reaction conditions and the results are sum-
Cs2CO3
K2CO3
K3PO4
NEt3
DMSO
DMSO
DMSO
DMSO
a General reaction conditions: iodobenzene (1.0 mmol), thiourea
(1.5 mmol), Cu catalyst (0.1 mmol), ligand (0.2 mmol) and 2
equiv. base in solvent (2.5 mL) at 90 ℃ under Ar for 24 h. b GC
yield.
*
E-mail: sanxiauqi@163.com
Received January 5, 2010; revised and accepted May 14, 2010.
Project supported by Chongqing Science and Technology Commission (No. 2008AC7128), Chongqing Municipal Education Commission (No.
KJ081102), and Ministry of Education of the People’s Republic of China “Spring Sunshine” Plan (No. Z2007-1-630010).
Chin. J. Chem. 2010, 28, 1441— 1443
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Qiao, Xie & Qi
FULL PAPER
tively as the catalyst and ligand in DMSO at 90 ℃.
Then, we screened a series of Cu salts and preliminary
results showed that Cu salts such as CuBr, CuI and
Cu2O were also effective when L-proline was used as
the ligand (Table 1, Entries 4—6). The most efficient
CuI was selected to examine the effect of the ligands.
Attempts to use 1,10-Phen (1,10-phenanthroline),
DMEDA (N,N′-dimethylethylenediamine), TMEDA (N,
N,N′,N′-tetramethylethylenediamine) and TMHD (2,2,
6,6-tetramethyl-3,5-heptanedione) resulted in low yields
(Table1, Entries 7—10). Further, we probed the solvent
effect and found that DMSO was considerably superior
to DMF, toluene, or dioxane (Table 1, Entries 11—13).
Finally, we found that the nature of the bases had a
pronounced impact on the reaction. Cs2CO3, K2CO3,
K3PO4, and NEt3 were all inferior to NaOBu-t (Table1,
Entries 14—17). Thus, the optimum results were ob-
tained when thiourea (1.5 equiv.) and aryl iodide (1.0
equiv.) were catalyzed by CuI (0.1 equiv.) in the pres-
ence of L-proline (0.2 equiv.) and using NaOBu-t (2.0
equiv.) as a base in DMSO at 90 ℃ under Ar for 24 h.
With optimized reaction conditions in hand, a num-
ber of aryl iodides were examined to explore the scope
of this reaction. As summarized in Table 2, we found
that the S-arylation reactions of thiourea with p-substi-
tuted aryl iodides were faster than those with
Continued
Yieldb/%
Entry
9
ArI
Product
I
SH
95
O2N
O2N
I
SH
SH
10
11
12
96
90
F3C
NC
F3C
NC
I
I
SH
HO
HO
90
91
O
O
I
SH
13
O
O
I
SH
SH
14
15
86
85
MeO
MeO
MeO
MeO
I
I
SH
SH
16
81
Table 2 Copper-catalyzed coupling of thiourea with aryl io-
didesa
H2N
H2N
H2N
H2N
I
17
18
82
83
I
SH
Entry
1
ArI
Product
Yieldb/%
86
I
SH
I
SH
19
80
90
I
I
I
SH
I
SH
2
3
4
90
90
82
20
N
N
SH
SH
a General reaction conditions: aryl iodide (1.0 mmol), thiourea
(1.5 mmol), CuI (0.1 mmol), L-proline (0.2 mmol) and 2 equiv.
NaOBu-t in DMSO (2.5 mL) at 90 ℃ under Ar for 24 h. b Iso-
lated yield.
o-substituted and m-substituted aryl halides (Table 2,
Entries 1— 5). As expected, the tolerance of the catalytic
system on aryl iodides counterpart was remarkable.
Substrates with electron-withdrawing groups were ef-
fectively converted into the desired S-aryl thiols in ex-
cellent yields (Table 2, Entries 6— 13). Electron-rich
group substituted aryl iodides and heteroaryl iodide
were also completely converted to the corresponding
S-aryl thiols in good yields (Entries 14— 20).
I
SH
5
83
I
SH
SH
SH
6
7
8
97
93
90
F
Cl
Br
F
Cl
Br
I
I
These results suggest that the reaction occurs by
oxidative addition followed by reductive elimination
(Scheme 1). The oxidative addition of the aryl iodide
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Chin. J. Chem. 2010, 28, 1441— 1443

Copper-Catalyzed Coupling of Thiourea with Aryl Iodides
with catalyst a can give intermediate b, which under-
goes reaction with thiourea to afford intermediate c.
Intermediate c can provide the C— S cross coupling
product d by reductive elimination, d (S-phenyl-iso-
thiuronium iodide) with base followed by acidification
with hydrochloric acid afforded e.
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Scheme 1 The proposed mechanism of copper-catalyzed cou-
pling of thiourea with aryl iodides
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In conclusion, we have developed a general, eco-
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catalyzed synthesis of aryl thiols from all kinds of aryl
iodides. Compared with documented methods, this reac-
tion does not employ toxic and expensive Pd or Ni salts,
and expensive ligands. On the other hand, the conven-
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Chin. J. Chem. 2010, 28, 1441— 1443
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