Ligand-free copper-catalyzed synthesis of asymmetrical thioethers by coupling aryl or alkyl halides using an acetyl thiourea precursor in wet polyethylene glyol (PEG 400)

Article abstract of DOI:10.1080/10426507.2014.906428

Asymmetrical diaryl or aryl alkyl thioethers can be prepared in good to excellent yields by coupling the appropriate aryl iodides and aryl or alkyl bromines using acetyl thiourea as a thiolprecursor, Cu₂O as a catalyst, KOH as a base, and PEG 400-H₂O as a solvent under ligand-free conditions.

Full text of DOI:10.1080/10426507.2014.906428

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Phosphorus, Sulfur, and Silicon and the Related
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Ligand-Free Copper-Catalyzed Synthesis of
Unsymmetrical Thioethers by Coupling Aryl or alkyl
Halides Using a Acetyl Thiourea Precursor in Wet
Polyethylene Glyol (PEG 400)
Baohua Zhanga, Lanxiang Shia, Ruixia Guoa & Juan Wanga
a College of Chemical Engineering, Shijiazhuang University, Shijiazhuang 050035, China
Accepted author version posted online: 07 Jul 2014.
To cite this article: Baohua Zhang, Lanxiang Shi, Ruixia Guo & Juan Wang (2014): Ligand-Free Copper-Catalyzed Synthesis of
Unsymmetrical Thioethers by Coupling Aryl or alkyl Halides Using a Acetyl Thiourea Precursor in Wet Polyethylene Glyol (PEG
400), Phosphorus, Sulfur, and Silicon and the Related Elements, DOI: 10.1080/10426507.2014.906428
To link to this article: http://dx.doi.org/10.1080/10426507.2014.906428
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Ligand-Free Copper-Catalyzed Synthesis of Unsymmetrical Thioethers by Coupling Aryl
or alkyl Halides Using a Acetyl Thiourea Precursor in Wet Polyethylene Glyol (PEG 400)
Baohua Zhang, Lanxiang Shi *, Ruixia Guo and Juan Wang
College of Chemical Engineering, Shijiazhuang University, Shijiazhuang 050035, China
We thank the Hebei province science and technology support program (grant no. 07215603D).
Address correspondence to Lanxiang Shi, College of Chemical Engineering, Shijiazhuang
University, Shijiazhuang 050035, China. E-mail: kedashilanxiang@126.com
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Abstract Unsymmetrical diaryl or aryl alkyl thioethers can be prepared in good to excellent
yields by coupling the appropriate aryl iodides and aryl or alkyl bromines using acetyl thiourea
as a thiol precursor, Cu2O as a catalyst, KOH as a base and PEG 400-H2O as a solvent under
ligand-free conditions.
S
O
S
S
(i) Cu2O,
wet PEG 400
Ar
Ar
Ar'
+
Ar-I
H3C
N
NH2
(ii) KOH,
Ar'-Br or Alk-Br
H
Alk
Key words
Unsymmetrical thioether, copper, acetyl thiourea, PEG, cross-coupling, catalysis
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INTRODUCTION
Unsymmetrical thioethers are important synthetic intermediates often found in biologically and
pharmaceutically active molecules, and polymeric materials.1 The traditional methods for the
synthesis of unsymmetrical thioethers often require harsh reaction conditions such as Grignard
reagents and elevated temperature,2 and are not suitable for molecules containing sensitive
functional groups. To overcome these drawbacks, palladium-,3-5 nickel-,6-7 copper-,8-11 cobalt-,12
indium-,13-14 and iron-based15-16 catalytic systems have been explored. These
transition-metal-catalyzed coupling of thiols with alkyl halides or aryl halides have overcome
these difficulties to a great extent. But, which methods have many disadvantages, like volatile,
foul-smelling and less available of arenethiols, which drawbacks make these methods are less
adoptable for the sustainable synthesis of various thioethers. Recently, efficient and odourless
preparative methods of unsymmetrical thioethers have been achieved by the replacement of
thiols with thiol precursors such as thiourea,17 thiolyanate,18 ethyl xanthagenate,19, 20
thioacetamide21 and thioacetate22. However, until now, new environmentally friendly methods
for preparation of unsymmetrical thioethers are still rarely reported.
The use of polyethylene glycols (PEGs) as a solvent in organic reactions has attracted much
attention due to the inexpensive, thermally stable, non-toxic, negligible vapor pressure and
environmentally benign media for chemical reactions. In addition, ligand-free methods have
been studied due to their advantages, such as high atom efficiency, simplified isolation of the
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product, and easy recovery of the catalysts. Herein, we report a new protocol for the synthesis of
unsymmetrical thioethers by coupling the appropriate aryl iodides and aryl or alkyl bromines
using acetyl thiourea as a thiol precursor, Cu2O as a catalyst, KOH as a base and PEG 400-H2O
as a solvent under ligand-free conditions.
RESULTS AND DISCUSSION
We initiated our study by reacting iodobenzene (1 mmol) with acetyl thiourea (1 mmol) in
the presence of 20 mol% Cu2O, and PEG 400 (4 mL) at 105℃. After 24h, KOH (3 mmol) and
p-bromoanisole (0.8 mmol) were added to the reaction mixture and the resulting mixture was
heated further for 24h. The reaction proceeded well and the desired product (4-methoxyphenyl)
(phenyl) sulfane was isolated in 46% yield.
In order to optimize the reaction conditions, several catalysts, solvents, and bases were
screened in above model reaction, the results summarized in Table 1. Using PEG 400 as a
solvent and KOH as a base, different copper catalysts were examined. The results shown that the
reactions catalyzed by copper compounds in various oxidation states were carried out smoothly,
and the desired products were obtained in moderate yields (Table 1, entries 1-4). In the absence
of a copper catalyst, no desired product was isolated (Table 1, entry 5). This has proven that the
presence of a copper catalyst was crucial for the reaction. Next, solvents were screened by using
Cu2O as a catalyst. Results show that PEG 400 was the best choice (Table 1, entry 1). Using H2O
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and aqueous solution of β-cyclodextrin as solvents, no desired product was formed (Table 1, 6
and 7). Seker et al. reported that glycol or 1,4-diol compound can serve as ligands in the
Cu-catalyzed synthesis of thioethers20. It can be speculated that PEG was likely to serve as a
ligand in the reaction. Surprisingly, when H2O was added to PEG 400, the reaction was
dramatically improved to give the coupling product in 81% yield (Table 1, entry 8).
Reducing the amount of H2O in PEG 400, the product yield decreased, however, increasing the
water content in PEG 400, the yield of product did not change (Table 1, entries 9 and 10).
Presumably, when H2O was introduced into the reaction mixture, hydrolysis of the reaction
intermediate may occur21. In addition, in the screening of the bases, the best yield was given by
KOH (Table 1, entry 8).
Therefore, our optimal reaction conditions were as follows: 10 mol% Cu2O as the catalyst,
aryl iodides (1 mmol) and Ar’-Br or Alk-Br (0.8 mmol) as the arylation reagents, and acetyl
thiourea as the sulfur source (1 mmol), PEG 400-H2O (10:1 ratio) as the solvent, and KOH as the
base at 105oC.
Having identified the best reaction conditions, we next examined the scope of the coupling
of acetyl thiourea with various aryl or alkyl halides (Table 2). The results shown that the
electronic property of different substituent on the aryl rings have little effect on this coupling
reaction, and aryl halides bearing both electron-withdrawing groups and electron-donating
groups worked well, products were obtained in 77-83% yields (Table 1, entries 1-5 and 8-9).
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Aryl iodides carrying an ortho substituent were also found to readily participate in the reaction.
For instance, 2-iodotoluene and 2-iodonitrobenzene gave isolated yield of 76% and 77%
respectively (Table 2, entries 6 and 7). Heteroaryl sulfides were also obtained with satisfactory
yields (Table 2, entries 10-11). Replace aryl bromides with alkyl bromides in the second iteration
could obtain excellent yields (Table 2, entries 12-15).
Based on the literatures21, 23, we have also proposed a general pathway for the reaction as
presented in Scheme 1.
In summary, we have introduced an efficient, versatile and odourless protocol for the
preparation of unsymmetrical thioethers by coupling the appropriate aryl iodides and aryl or
alkyl bromines using acetyl thiourea as a thiol precursor, Cu2O as a catalyst in wet polyethylene
glycol (PEG 400) without the use of any external ligands. Various diaryl thioethers and aryl alkyl
thioethers were obtained in good to excellent yields. Further applications to the synthesis of
biologically molecules are in progress.
EXPERIMENTAL
1H and 13C spectra were recorded in CDCl3 on a 300 MHz instrument at 300 MHz (1H) and
75 MHz (13C) with TMS as internal standard.
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General Procedure for Preparation of Thioether
Cu2O (10 mol %), aryl iodide (1 mmol), acethyl thiourea (118 mg, 1 mmol) were placed in
a small round-bottomed flask. PEG 400 (4 mL) and H2O (0.4 mL) were then added together. The
mixture was stirred for 24h at 105 under a nitrogen atmosphere. Then KOH (159 mg, 3mmol)
and Ar’-Br or Alk-Br (0.8 mmol) were added and the reaction mixture was stirred for 24h. After
completion of the reaction, the reaction mixture was cooled to room temperature and poured into
10 mL of saturated sodium chloride aqueous solution and extracted with ethyl acetate (2×5 mL),
dried over MgSO4 and concentrated. Purification by silica gel chromatography afforded the
desired products. The Supplemental Materials contains characterization data of the known
products from Table 2.
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Ar-I
Cu2O
-IH2N+
Ar
H2N
S
S
Ar-S-Ar' or
Ar-S-Alk
H3COCHN
H3COCHN
-SAr
KOH
KI
Cu2O
Ar'-Br
or Alk-Br
HN
H3COCHN
S
Ar
Ar
S
NHCOCH3
H2N
O-
Ar
S
-OH
-HN
NHCOCH3
OH
Scheme 1 Possible mechanism
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Table 1 Optimization of Catalysts, Solvents and Based for Synthesis of Thioethersa
I
S
O
H
S
S
N
CH3
base
solvent
+
H3C
N
NH2
p-MeOPhBr
105℃
105℃
H
NH
O
OMe
entry
catalyst
Cu2O
CuI
CuO
Cu(OAc)2
-
solvent
base
KOH
KOH
KOH
KOH
KOH
KOH
Yield (%)b
1
2
3
4
5
6
PEG 400
PEG 400
PEG 400
PEG 400
PEG 400
46
43
45
42
0
Cu2O
H2O
Aqueous
0
solution of
β-cyclodextrin
PEG 400-H2O
(20 : 1 ratio)
PEG 400-H2O
(25 : 1 ratio)
PEG 400-H2O
(10 : 1 ratio)
PEG 400-H2O
(10 : 1 ratio)
PEG 400-H2O
(10 : 1 ratio)
PEG 400-H2O
(10 : 1 ratio)
7
Cu2O
KOH
0
8
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
KOH
KOH
81
72
81
78
62
70
9
10
11
12
13
KOH
K3PO3
Na2CO3
K2CO3
a Reaction conditions: iodobenzene (1 mmol), catalyst (10 mol%), solvent (4 mL), base (3 mL),
p-MeOPhBr (0.8 mmol), acethyl thiourea (1 mmol), 105 ; b Isolated yield.
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Table 2 Copper Catalyzed Synthesis of Thioethers with Acetyl Thiourea and Various Aryl or
Alkyl Halides a
S
O
S
S
(i) Cu2O
Ar
Ar
Ar'
+
Ar-I
H3C
N
NH2
H
(ii) KOH, Ar'-Br or Alk-Br
Alk
entry
1
Ar-I
Ar’-Br or Alk-Br
product
yield (%)b
81
ref.c
22
Br
S
I
OCH3
H3CO
S
I
Br
2
3
79
77
83
80
76
77
83
80
80
73
19
19
19
19
24
24
24
24
19
19
O2N
Cl
O2N
S
I
Br
Br
Br
Br
Cl
I
S
4
H3C
H3CO
H3C
H3CO
I
S
5
I
S
6
CH3
S
CH3
I
Br
7
NO2
NO2
I
Br
S
8
NO2
F
O2N
Br
I
I
I
S
9
F
N
S
10
11
N
S
Br
Ph
S
Br
Ph
S
I
C5H11Br
C5H11Br
12
13
88
82
19
24
S
C5H11
I
S
C5H11
NO2
NO2
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I
S
Br
14
80
84
24
24
H3C
H3C
I
S
Br
15
H3C
H3C
a Reaction conditions: aryl iodide (1 mmol), Cu2O (10 mol%), PEG 400-H2O (10:1 ratio, 4 mL),
KOH (3 mmoL), Ar’-Br or Alk-Br (0.8 mmol), acethyl thiourea (1 mmol), 105 ; b Isolated
yield; cReferences of product characteristics.
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