Copper oxide nanoparticles catalyzed synthesis of aryl sulfides via cascade reaction of aryl halides with thiourea

Article abstract of DOI:10.1016/j.tetlet.2011.03.070

Recyclable copper oxide nanoparticles catalyzed simple and highly efficient protocol for the synthesis of symmetrical aryl sulfides was developed by the cross-coupling of aromatic halides with inexpensive and commercially available thiourea which was used as an effective sulfur surrogate. The present cross-coupling protocol of thiourea, via cascade reaction with various substituted aryl halides, producing desired aryl sulfides, has an added advantage of avoiding foul-smelling thiols.

Full text of DOI:10.1016/j.tetlet.2011.03.070

Tetrahedron Letters 52 (2011) 2679–2682
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper oxide nanoparticles catalyzed synthesis of aryl sulfides via cascade
reaction of aryl halides with thiourea
⇑
K. Harsha Vardhan Reddy, V. Prakash Reddy, J. Shankar, B. Madhav, B. S. P. Anil Kumar, Y. V. D. Nageswar
Organic Chemistry Divison-I, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Recyclable copper oxide nanoparticles catalyzed simple and highly efficient protocol for the synthesis of
symmetrical aryl sulfides was developed by the cross-coupling of aromatic halides with inexpensive and
commercially available thiourea which was used as an effective sulfur surrogate. The present cross-cou-
pling protocol of thiourea, via cascade reaction with various substituted aryl halides, producing desired
aryl sulfides, has an added advantage of avoiding foul-smelling thiols.
Received 23 December 2010
Revised 10 March 2011
Accepted 15 March 2011
Available online 22 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Aryl halides
Thiourea
Aryl sulfides
Cross-coupling
Copper oxide
During the last few decades, aryl sulfides and their derivatives
are found in numerous biological, pharmaceutical, and material
science applications.1 The classical methods for the synthesis of
aryl sulfides require harsh reaction conditions, such as strong bases
and elevated temperatures. Also the reduction of sulfones or sulf-
oxides involves strong reducing agents, such as DIBAL-H or LiAlH4.2
To overcome these difficulties, transition metal catalyzed coupling
systems utilizing palladium,3 nickel,4 copper,5 iron,6 indium,7 lan-
thanum,8 and cobalt9 have been developed. Even though several
methodologies have been designed for the synthesis of aryl sul-
fides, most of these reactions include the coupling between thiols
and an aryl halide. The direct use of volatile, hazardous, and foul-
smelling thiols is still the main drawback, which leads to unavoid-
able environmental and safety problems. Hence it is desirable to
find novel alternate catalytic protocols specially designed to avoid
volatile and foul-smelling thiols to access such highly useful tar-
gets like aryl sulfides. Recently Zhou and co-workers reported an
efficient C–S bond formation between potassium thiocyanate and
aryl halides by a copper catalyst in water by using ligands.10
Recently, heterogeneous catalysts have attracted the attention
of researchers due to their economic and industrial significance
and published reports indicate that they scored over homogeneous
catalysts. Among these, nanoscale heterogeneous catalysts are
highly preferred as they offer high surface area and low-coordi-
nated sites, which are responsible for the higher catalytic activ-
ity,11 having the advantage of easy product purification and
reusability of the catalyst.
In continuation of our interest in the field of cross-coupling
reactions,12 we report herein CuO nanoparticles catalyzed cascade
reactions of thiourea and aryl halides forming symmetrical diphe-
nyl sulfides under ligand-free conditions. However, to the best of
our knowledge, this is the first report on the synthesis of symmet-
rical diaryl sulfides in the absence of any ligand or co-metal
catalyst.
Initially, iodobenzene and thiourea were chosen as the model
substrates to optimize the reaction conditions, such as various cop-
per sources, catalysts, bases, solvents, and temperature under
nitrogen atmosphere (Table 1, Scheme 1). First, several copper cat-
alysts were screened and CuO nanoparticles were proven to be pre-
eminent for this tandem reaction (Table 1, entry 2). The effect of
solvents was also investigated and it was observed that the desired
product was not obtained in the solvents toluene and THF (Table 1,
entries 7 and 12). However, the reaction was highly effective with
polar aprotic solvents such as DMSO and DMF (Table 1, entries 2,
8). Among various bases screened (e.g., KOH, Cs2CO3, Na2CO3,
NaOH), Cs2CO3 was most effective in DMSO solvent (Table 1, entry
2). The control experiment confirmed that the reaction did not
occur in the absence of the catalyst (Table 1, entry 10) as well as
the base (Table 1, entry 11). The reaction when conducted at room
temperature and 50 °C, the yields observed were very low (Table 1,
entries 5 and 6). The ideal temperature for the reaction was found
to be 110 °C.
While expanding the scope of the reaction, the cross-coupling of
various substituted thioureas with different aryl halides was also
⇑
Corresponding author.
E-mail address: dryvdnageswar@gmail.com (Y.V.D. Nageswar).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.070

2680
K. H. V. Reddy et al. / Tetrahedron Letters 52 (2011) 2679–2682
Table 1
Table 3
Screening of copper-catalyzed synthesis of aryl sulfidesa
C–S cross-coupling of aryl halides with thioureaa
I
S
S
S
catalyst
solvent, base
CuO, DMSO, Cs2CO3
NH2
Ar
X
Ar
S
Ar
H2N
H2N
NH2
15 h, 110°C
Yieldb (%)
Entry Aryl halide
Product
Yieldb
(%)
Entry
Copper source
Base
Solvent
Temp (°C)
1
2
3
4
5
6
7
8
Nano CuO
Nano CuO
Nano CuO
Nano CuO
Nano CuO
Nano CuO
Nano CuO
Nano CuO
Nano CuO
––
KOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Toluene
DMF
Toluene
DMSO
DMSO
THF
110
110
110
110
50
20
97
61
Trace
49
26
0
Cs2CO3
Na2CO3
NaOH
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
KOH
KOH
––
Cs2CO3
Cs2CO3
Cs2CO3
I
S
S
1
97
70c
93
91
Br
2
rt
110
110
110
110
110
110
110
110
I
S
68
0
3
4
9
10
11
12
13
14
0c
I
S
Nano CuO
Nano CuO
CuO
0d
0
DMSO
DMSO
60
67
I
S
Cu2O
5
6
7
8
96
73c
87
89
a
MeO
MeO
OMe
Reaction conditions: iodo benzene (2.0 mmol), thiourea (1.2 mmol), catalyst
(5.0 mol %), base (2.0 equiv), solvent (2.0 mL), 15 h.
Br
S
b
Isolated yield.
In the absence of catalyst.
In the absence of base.
c
MeO
O2N
MeO
O2N
OMe
NO2
d
S
I
S
I
S
I
S
CuO nano
H2N
NH2 Cs2CO3, DMSO
F
F
F
I
Scheme 1. CuO nanoparticles catalyzed synthesis of aryl sulfides.
S
9
88
Table 2
Effect of different substituted thiourea on the synthesis of aryl sulfidesa
I
S
10
11
90
85
Ph
O
Ph
O
O
Ph
Entry
Aryl halide
Thioureas
Yieldb (%)
I
S
S
S
I
1
2
97
93
H2N
NH2
CF3
H2N
H2N
NH2
I
I
I
I
12
82
F3C
F3C
S
3
4
5
6
89
86
86
81
I
I
N
H
NH2
S
13
14
83
I
S
S
S
S
S
S
S
S
59c
Br
I
S
N
H
NH2
15
79
S
S
S
I
S
S
16
17
75
N
H
N
H
N
7
8
81
75
H
I
N
H
NH2
Br
S
N
N
N
60c
I
N
N
N
N
N
N
I
S
a
Reaction conditions: iodo benzene (2.0 mmol), thioureas (1.2 mmol), nano CuO
(5.0 mol %), Cs2CO3 (2.0 equiv), DMSO (2.0 mL), 110 °C, 15 h.
18
19
78
79
N
N
HO
N
S
b
Isolated yield.
HO
I
OH
a
investigated under optimized conditions (Table 2), providing the
corresponding diaryl sulfides in excellent yields. Among these,
thiourea appeared to be the best choice because of commercial
availability and economic affordability for the synthesis of aryl sul-
fides (Table 2, entry 1).
Reaction conditions: aryl halides (2.0 mmol), thiourea (1.2 mmol), nano CuO
(5.0 mol %), Cs2CO3 (2.0 equiv), DMSO (2.0 mL), 110 °C, 15 h, under a nitrogen
atmosphere.
b
Isolated yield.
After 24 h.
c
In general, all the reactions were very clean, and the diaryl
efficiently cross coupled iodobenzenes having electron donating
groups (e.g., Me, Et, and OMe) with thiourea to produce the corre-
sulfides were obtained in high yields (Table 3).13 This protocol

K. H. V. Reddy et al. / Tetrahedron Letters 52 (2011) 2679–2682
2681
S
S
Et
Et
I
I
S
CuO, DMSO, Cs2CO3
NH2
55%
48%
H2N
15 h,110°C
Et
S
Et
31%
Scheme 2. CuO nanoparticles catalyzed synthesis of aryl unsymmetrical and symmetrical sulfides.
Table 4
References and notes
Recycling of CuO nanoparticles
1. (a) Alcaraz, M.-L.; Atkinson, S.; Cornwall, P.; Foster, A. C.; Gill, D. M.;
Humphries, L. A.; Keegan, P. S.; Kemp, R.; Merifield, E.; Nixon, R. A.; Noble, A.
J.; Obeirne, D.; Patel, Z. M.; Perkins, J.; Rowan, P.; Sadler, P.; Singleton, J. T.;
Tornos, J.; Watts, A. J.; Woodland, I. A. Org. Process Res. Dev. 2005, 9, 555; (b) Liu,
G.; Link, J. T.; Pei, Z.; Reilly, E. B.; Leitza, S.; Nguyen, B.; Marsh, K. C.; Okasinski,
G. F.; von Geldern, T. W.; Ormes, M.; Fowler, K.; Gallatin, M. J. Med. Chem. 2000,
43, 4025; (c) Wang, Y.; Chackalamannil, S.; Chang, W.; Greenlee, W.; Ruperto,
V.; Duffy, R. A.; Mcquade, R.; Lachowicz, J. E. Bioorg. Med. Chem. Lett. 2001, 11,
891; (d) Bonnet, B.; Soullez, D.; Girault, S.; Maes, L.; Landry, V.; Davioud-
Charvet, E.; Sergheraert, C. Bioorg. Med. Chem. 2000, 8, 95; (e) Baird, C. P.;
Rayner, C. M. J. Chem. Soc., Perkin Trans. 1 1998, 1973; (f) Procter, D. J. J. Chem.
Soc., Perkin Trans. 1 2001, 335.
Recycles
Yield (%)
Catalyst recoverya (%)
1
2
3
4
97
95
91
89
96
93
91
88
a
Reaction conditions: aryl halides (2.0 mmol), thiourea (1.2 mmol), nano CuO
(5.0 mol %), Cs2CO3 (2.0 equiv), DMSO (2.0 mL), 110 °C, 15 h, under a nitrogen
atmosphere.
2. (a) Lindley, J. Tetrahedron 1984, 40, 1433; (b) Yamamoto, T.; Sekine, Y. Can. J.
Chem. 1984, 62, 1544; (c) Hickman, R. J. S.; Christie, B. J.; Guy, R. W.; White, T. J.
Aust. J. Chem. 1985, 38, 899; (d) Bierbeek, A. V.; Gingras, M. Tetrahedron Lett.
1998, 39, 6283.
3. (a) Murata, M.; Buchwald, S. L. Tetrahedron 2004, 60, 7397; (b) Mispelaere-
Canivet, C.; Spindler, J.-F.; Perrio, S.; Beslin, P. Tetrahedron 2005, 61, 5253; (c)
Itoh, T.; Mase, T. Org. Lett. 2004, 6, 4587; (d) Fernandez-Rodrıguez, M. A.; Shen,
Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 218; (e) Lee, J.-Y.; Lee, P. H. J. Org.
Chem. 2008, 73, 7413.
sponding aryl sulfides in excellent yields (Table 3, entries 3–5),
whereas in the presence of electron withdrawing group (NO2) a
slight decrease in the yield of the diaryl sulfide (Table 3, entry 7)
was observed. In the case of aryl iodide with a free amino group
the reaction proceeded without the need of a protecting group
and the desired product was obtained in good yields (Table 3, entry
11). It was observed that iodobenzene was more reactive. Conse-
quently, cross-coupling reactions with fluoro substituted aryl io-
dides exhibited an interesting chemo selectivity proceeding
exclusively at the iodo group (Table 3, entry 8). Utilizing optimized
conditions, the coupling process was investigated with several het-
ero aromatic iodides resulting in the corresponding diaryl sulfides
in impressive yields (Table 3, entries 13, 15, 16, and 18). In the case
of the reaction of aryl bromides and hetero aromatic bromides
with thiourea the process required longer reaction time to obtain
reasonable yield of diaryl sulfides (Table 3, entries 2, 6, 14, and 17).
This protocol was also applied for the cross-coupling reaction
between two different aryl halides by using iodobenzene and 4-
ethyliodobenzene and the corresponding symmetric products
were obtained in high yields when compared to unsymmetrical
sulfide (Scheme 2).
After each cycle, the reaction mixture was allowed to cool, and
the catalyst was recovered by simple centrifugation, washing with
ethyl acetate, acetone and then drying in vacuo. The recovered CuO
was used directly in the next cycle. The catalyst was found to be
recyclable without the loss of catalytic activity up to four cycles
(Table 4).
In conclusion, we have developed a recyclable CuO nanoparti-
cles catalyzed synthesis of symmetrical diaryl sulfides under li-
gand-free conditions in the absence of any additive. The reaction
employs a very simple catalyst system, having functional group
tolerance, and resulting in good to excellent yields. The advantages
of the novel and facile protocol are precluding volatile, foul smell-
ing, and toxic thiols as well as utilizing economically affordable,
recyclable and air stable catalyst under ligand-free conditions.
4. (a) Taniguchi, N. J. Org. Chem. 2004, 69, 6904; (b) Jammi, S.; Barua, P.; Rout, L.;
Saha, P.; Punniyamurthy, T. Tetrahedron Lett. 2008, 49, 1484; (c) Takagi, G.
Chem. Lett. 1986, 15, 1379–1380.
5. (a) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517; (b) Chen, Y.-J.; Chen,
H.-H. Org. Lett. 2006, 8, 5609; (c) Taniguchi, N. J. Org. Chem. 2007, 72, 1241; (d)
Sperotto, E.; Klink, G. P. M. V.; De Vries, J. G.; Koten, G. V. J.Org. Chem. 2008, 73,
5625; (e) Rout, L.; Saha, P.; Jammi, S.; Punniyamurthy, T. Eur. J. Org. Chem. 2008,
640; (f) Herrero, M. T.; SanMartin, R.; Domınguez, E. Tetrahedron 2009, 65,
1500; (g) Prasad, D. J. C.; Naidu, A. B.; Sekar, G. Tetrahedron Lett. 2009, 50, 1411;
(h) Wang, H.; Jiang, L.; Chen, T.; Li, Y. Eur. J. Org. Chem. 2010, 12, 2324; (i) She, J.;
Jiang, Z.; Wang, Y. Tetrahedron Lett. 2009, 50, 593; (j) Basu, B.; Mandal, B.; Das,
S.; Kundu, S. Tetrahedron Lett. 2009, 50, 5523; (k) Feng, Y.; Wang, H.; Sun, F.; Li,
Y.; Fu, X.; Jin, K. Tetrahedron 2009, 65, 9737; (l) Jogdand, N. R.; Shingate, B. B.;
Shingare, M. S. Tetrahedron Lett. 2009, 50, 6092; (m) Feng, Y.-S.; Li, Y.-Y.; Tang,
L.; Wu, W.; Xu, H.-J. Tetrahedron Lett. 2010, 51, 2489; (n) Bates, C. G.; Gujadhur,
R. K.; Venkataraman, D. Org. Lett. 2002, 4, 2803; (o) Savarin, C.; Srogl, J.;
Liebeskind, L. S. Org. Lett. 2002, 4, 4309; (p) Ranu, B. C.; Saha, A.; Jana, R. Adv.
Synth. Catal. 2007, 349, 2690; (q) Chen, C.-K.; Chen, Y.-W.; Lin, C.-H.; Lin, H.-P.;
Lee, C.-F. Chem. Commun. 2010, 46, 282; (r) Rout, L.; Sen, T. K.; Punniyamurthy,
T. Angew. Chem., Int. Ed. 2007, 46, 5583.
6. Correa, A.; Carril, M.; Bolm, C. Angew. Chem., Int. Ed. 2008, 47, 2880.
7. Reddy, V. P.; Swapna, K.; Kumar, A. V.; Rao, K. R. J. Org. Chem. 2009, 74, 3189; (b)
Reddy, V. P.; Kumar, A. V.; Swapna, K.; Rao, K. R. Org. Lett. 2009, 11, 1697.
8. Murthy, S. N.; Madhav, B.; Reddy, V. P.; Nageswar, Y. V. D. Eur. J. Org. Chem.
2009, 5902.
9. Wong, Y.-C.; Jayanth, T. T.; Cheng, C.-H. Org. Lett. 2006, 8, 5613.
10. Ke, F.; Qu, Y.; Jiang, Z.; Li, Z.; Wu, D.; Zhou, X. doi: 10.1021/ol102784c.
11. (a) Pacchioni, G. Surf. Rev. Lett. 2000, 7, 277; (b) Knight, W. D.; Clemenger, K.; de
Heer, W. A.; Saunders, W. A. M.; Chou, Y.; Cohen, M. L. Phys. Rev. Lett. 1984, 52,
2141; (c) Kaldor, A.; Cox, D.; Zakin, M. R. Adv. Chem. Phys. 1988, 70, 211.
12. (a) Reddy, V. P.; Swapna, K.; Kumar, A. V.; Rao, K. R. J. Org. Chem. 2009, 74, 3189;
(b) Swapna, K.; Kumar, A. V.; Reddy, V. P.; Rao, K. R. .J. Org. Chem. 2009, 74,
7514; (c) Reddy, V. P.; Kumar, A. V.; Swapna, K.; Rao, K. R. Org. Lett. 2009, 11,
951; (d) Reddy, V. P.; Kumar, A. V.; Swapna, K.; Rao, K. R. Synlett 2009, 2783; (e)
Reddy, V. P.; Kumar, A. V.; Rao, K. R. Chem. Lett. 2010, 39, 212; (f) Reddy, V. P.;
Kumar, A. V.; Rao, K. R. Tetrahedron Lett. 2010, 51, 3181; (g) Swapna, K.;
Murthy, S. N.; Nageswar, Y. V. D. Eur. J. Org. Chem. 2010, 6, 678.
13. General procedure for the synthesis of aryl sulfides:
To a stirred solution of aryl halides (2.0 mmol) and thiourea (1.2 equiv) in dry
DMSO (2.0 mL) at rt was added nano CuO (5.0 mol %) followed by Cs2CO3
(2.0 equiv) and heated at 110 °C for 15 h. The progress of the reaction was
monitored by TLC. After the reaction was complete, the reaction mixture was
allowed to cool, and a 1:1 mixture of ethyl acetate/water (20 mL) was added.
The combined organic extracts were dried with anhydrous Na2SO4. The solvent
and volatiles were completely removed under vacuum to give the crude
product, which was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate, 9:1) to afford the corresponding coupling
product in excellent yields.
Acknowledgment
We thank CSIR, New Delhi, for the award of fellowships.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.070.
Recycling of the catalyst:

2682
K. H. V. Reddy et al. / Tetrahedron Letters 52 (2011) 2679–2682
after the reaction was complete, the reaction mixture was allowed to cool, and
J = 8.3 Hz); 13C NMR (75 MHz, CDCl3, TMS): d = 148.8, 136.7, 130.7, 125.6,
122.7; mass (EI): m/z 276 [M]+; Anal. calcd for: (C12H8N2O4S) C, 52.17; H, 2.92;
S, 11.61; N, 10.14; found: C, 52.12; H, 2.86; S, 11.55; N, 10.9.
a 1:1 mixture of ethyl acetate/water (2.0 mL) was added and CuO was removed
by centrifugation. After each cycle, the catalyst was recovered by simple
centrifugation, washing with deionized water and ethyl acetate and then
drying in vacuo. The recovered nano CuO was used directly in the next cycle.
Data of representative examples:
4,40-Thiodianiline (Table 3, entry 11): brown solid; mp 104–105 °C; 1H NMR
(300 MHz, CDCl3, TMS): d = 7.10 (d, 4H, J = 8.68 Hz), 6.52 (d, 4H, J = 8.68 Hz),
3.51 (br s, 4H); 13C NMR (75 MHz, CDCl3, TMS): d = 145.5, 133.8, 132.6, 124.8,
115.6; mass (EI): m/z 216 [M]+; Anal. calcd for: (C12H12N2S) C, 66.63; H, 5.59; N,
12.95; S, 14.82; Found: C, 66.61; H, 5.58; N, 12.92; S, 14.81.
Dip-tolylsulfane (Table 3, entry 3): yellow oil;1H NMR (200 MHz, CDCl3, TMS):
d = 7.21 (d, 4H, J = 8.0 Hz), 7.06 (d, 4H, J = 8.0 Hz), 2.32 (s, 6H); 13C NMR
(50 MHz, CDCl3, TMS): d = 136.7, 132.81, 131.0, 129.8, 96.1.
Dithiophen-3-ylsulfane (Table 3, entry 15): yellow oil; 1H NMR (300 MHz, CDCl3,
TMS): d = 7.31–7.25 (m, 2H), 7.17–7.11(m, 2H), 6.96–6.94 (m, 2H); 13C NMR
(75 MHz, CDCl3, TMS): d = 129.6, 126.4, 124.7; mass (EI): m/z 197 [M]+; Anal.
calcd for: (C8H6S3) C, 48.45; H, 3.05; S, 48.50; found: C,48.42; H,3.02; S,48.47.
Dipyrimidin-5-ylsulfane (Table 3, entry 17): colorless oil; 1H NMR (300 MHz,
CDCl3, TMS): d = 9.15 (s, 2H), 8.74(s, 4H); 13C NMR (75 MHz, CDCl3, TMS):
d = 158.6, 157.7, 129.8; mass (EI): m/z 190 [M]+; Anal. calcd for: (C8H6N4S) C,
50.51; H, 3.18; N, 29.45; S, 16.86; found: C, 50.45; H, 3.13; N, 29.41; S, 16.81.
Bis(4-ethylphenyl)sulfane (Table 3, entry 4): colorless oil; 1HNMR (300 MHz,
CDCl3, TMS): d = 7.21(d, 4H, J = 7.8 Hz), 7.07 (d, 4H, J = 7.8 Hz), 2.62–2.52 (m,
4H), 1.26 (t, 6H, J = 7.8 Hz);13C NMR (75 MHz, CDCl3, TMS): d = 143.1, 132.7,
131.0, 128.6, 28.3, 15.4; mass (EI): m/z 242 [M]+; Anal. calcd for: (C16H18S) C,
79.29; H, 7.49; S, 13.23; found: C,79.22; H,7.42; S,13.19.
Bis(3-nitrophenyl)sulfane (Table 3, entry 7): pale yellow oil; 1H NMR (300 MHz,
CDCl3, TMS): d = 8.19–8.15 (m, 4H), 7.65 (d, 2H, J = 8.3 Hz), 7.55 (t, 2H,