Copper oxide nanoparticles supported on graphene oxide-Catalyzed S-arylation: An efficient and ligand-free synthesis of aryl sulfides

Article abstract of DOI:10.1002/adsc.201300416

Copper oxide nanoparticles that are supported on graphene oxide as a catalytic system have been utilized for ligand-free and solvent-free C-S cross-coupling reactions with weak bases such as tri- ethylamine. Symmetrical/unsymmetrical aryl sulfides have been synthesized by the coupling of different aryl halides with aromatic as well as aliphatic sulfides. Surprisingly, aryl chlorides also well reacted with different types of sulfides in the presence of dimethyl sulfoxide and cesium carbonate. Besides, this catalytic system is suitable for the synthesis of phenothiazines via cascade C-S and C-N cross-coupling of ortho-dihalides and ortho-aminobenzothiazoles. In addition, this alternative approach is extremely useful for the synthesis of a variety of symmetrical diaryl sulfides by using thiourea as a sulfur source that is devoid of the foul smell of thiols. Indeed, the calculated E-factor value of our present protocol is 2.52. Furthermore, this protocol is particularly attractive as an environmentally benign and practical method for the synthesis of different aryl sulfides. Moreover, the heterogeneous catalytic system described in this process represents not only a greener approach but retains its significant activity for up to six catalytic cycles.

Full text of DOI:10.1002/adsc.201300416

FULL PAPERS
DOI: 10.1002/adsc.201300416
Copper Oxide Nanoparticles Supported on Graphene Oxide-
Catalyzed S-Arylation: An Efficient and Ligand-Free Synthesis
of Aryl Sulfides
a,
a
a
b
Ahmed Kamal, * Vunnam Srinivasulu, J. N. S. R. C Murty, Nagula Shankaraiah,
c
a,b
a
Narayana Nagesh, T. Srinivasa Reddy, and A. V. Subba Rao
Medicinal Chemistry & Pharmacology, CSIR – Indian Institute of Chemical Technology, Hyderabad – 500 007, India
a
Fax : (+91)-40-2719-3189; phone: (+91)-40-2719-3157; e-mail: ahmedkamal@iict.res.in
b
c
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad
500 037, India
CSIR – Centre for Cellular and Molecular Biology, Hyderabad – 500 007, India
–
Received: May 11, 2013; Revised: June 21, 2013; Published online: August 13, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300416.
Abstract: Copper oxide nanoparticles that are sup- useful for the synthesis of a variety of symmetrical
ported on graphene oxide as a catalytic system have diaryl sulfides by using thiourea as a sulfur source
been utilized for ligand-free and solvent-free CÀS that is devoid of the foul smell of thiols. Indeed, the
cross-coupling reactions with weak bases such as tri- calculated E-factor value of our present protocol is
ACHTUNGTRENNUNGe thylamine. Symmetrical/unsymmetrical aryl sulfides 2.52. Furthermore, this protocol is particularly attrac-
have been synthesized by the coupling of different tive as an environmentally benign and practical
aryl halides with aromatic as well as aliphatic sul- method for the synthesis of different aryl sulfides.
fides. Surprisingly, aryl chlorides also well reacted Moreover, the heterogeneous catalytic system de-
with different types of sulfides in the presence of di- scribed in this process represents not only a greener
methyl sulfoxide and cesium carbonate. Besides, this approach but retains its significant activity for up to
catalytic system is suitable for the synthesis of phe- six catalytic cycles.
nothiazines via cascade CÀS and CÀN cross-coupling
of ortho-dihalides and ortho-aminobenzothiazoles. In Keywords: aryl halides; CÀS cross-coupling; CuO
addition, this alternative approach is extremely nanoparticles; graphene oxide; thiols
Introduction
the traditional method of CÀS cross-coupling reaction
which usually requires harsh reaction conditions and
Catalytic methods for CÀS bond formation are of polar solvents such as HMPA, considerable efforts
[
6]
considerable importance due to the great demand in have been made in the past decades.
[
1]
[2]
organic synthesis, pharmaceutical industry, and as
In the last few years, TMC systems including metals
[
3]
well in material sciences. For example, the aryl sul- like Pd, Ni, Fe, Cu, Co and, very recently, In and Bi
fide unit is a common motif found in numerous drugs have also gained much interest that resulted in the de-
[
7]
for the treatment of a variety of diseases such as Alz- velopment of few methods for CÀS bond formation.
heimerꢀs, Parkinsonꢀs, cancer, HIV, diabetes and in- In addition, a variety of sulfur reagents was success-
[4]
flammation. However, the transition metal-catalyzed fully used as effective sulfur surrogates for the synthe-
[
8]
(
TMC) CÀS cross-coupling reaction is not much stud- sis of symmetrical aryl sulfides. Moreover, palladi-
ied compared to the corresponding other carbon-het- um-based catalytic systems require the use of toxic bi-
eroatom bonds such as CÀN, CÀO, CÀP, due to the dentate phosphines or diverse organophosphane de-
[
9]
strong coordination nature of the sulfur atom. More- rivatives, and are often air sensitive. On the other
over, it acts as a poison and completely suppresses hand, recent catalytic systems employing Ni, Fe, Co
[
5]
the activity of the catalyst. Indeed, disulfide forma- and In have mediated thioether bond formation be-
[
10]
tion in particular by oxidative coupling of thiols is tween aryl halides and thiols. Amongst all the tran-
also one of the major limiting factors in this area. In sition metals, Cu is predominantly attractive due to its
order to overcome these difficulties and to replace special redox properties, polarizability and cost-effec-
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[
11]
[19]
tiveness in comparison to other metal catalysts. In active transition metals. To date only few reports of
fact, these methods employing heterogeneous systems GO or CDG based catalytic systems have been re-
offer several advantages over homogeneous systems ported and they have proved to be highly efficient
[
20]
with respect to ease of recovery, recycling as well as catalysts. Indeed, the presence of various functional
minimization of environmental waste and clean reac- groups on GO could act as nucleation centers to form
tion products without contamination of active NP:GO nanocomposites and form intermolecular hy-
[
12]
metals.
Next, various commercially available and drogen bonds or coordination bonds, acting as anchor
[
21]
some of the specially synthesized supported metal sites for the crystallites to grow. Herein, our contin-
nanoparticles
[11a,c]
proved to be very efficient and con- ued interest in green chemistry research prompted us
venient systems as they have some advantages like to explore the scope of developing a greener process
avoiding the use of stoichiometric reagents, toxic li- towards CÀS cross-coupling reaction. In this context,
gands, having a minimized environmental factor (E- we have selected GO as support and as well have de-
[
13]
factor), and employing mild reaction conditions.
veloped a new protocol for the coupling reaction of
These recently developed methods are considered thiols with various aryl halides under ligand- and sol-
convenient over existing methods, however, certain vent-free conditions by employing the CuO nanopar-
limitations still remain like the requirement of ticles on GO (CuO@GO) as a catalyst. Moreover,
a strong base, that might seriously limit the tolerance this high catalytic activity under solvent-free condi-
towards base-sensitive functional groups as well as tions is mainly attributed to the large specific surface
polar solvents and longer reaction times. In addition, area of GO. Furthermore, we have calculated the E-
these catalytic systems are not well studied for sub- factor value for our protocol and compared it with
strates like aryl bromides and aryl chlorides and as the other catalytic systems reported in the literature.
the E-factor is high, they cannot be considered eco- Additionally, this catalytic system has also been suc-
friendly. Therefore, in order to minimize the draw- cessfully utilized for the synthesis of phenothiazines.
backs of the existing methods it is highly desirable to
develop an environmentally benign and as well effi-
cient catalytic system for CÀS bond formation.
Results and Discussion
In recent years, solvent-free organic synthesis is an
emerging area that is very useful in the context of The powder X-ray diffraction (XRD) pattern of the
combinatorial and sustainable chemistry. A bench- synthesized CuO@GO has depicted in Figure 1. It
marking exercise performed by the GCI Pharmaceuti- supports a single-phase with a monoclinic structure
cal Round Table revealed that solvents are the main and the positions of peaks are in good agreement
reason for the unsatisfactory E-factor and generate with the reported values (JCPDS). Moreover, the
[
14]
more organic waste in a reaction process. Indeed, it XRD pattern suggests that the CuO@GO nanocom-
has been explained by GlaxoSmithKline workers that posite products were successfully formed and the
ca. 85% of the total mass of chemicals involved in almost complete loss (very less in intense compared
[
15]
pharmaceutical manufacture consists of solvents.
with CuO peaks) of the regular reflection peak (001)
Consequently, pharmaceutical companies are focusing of GO indicated the change in its regular layered
their efforts to minimize the use of solvents or to de-
velop solvent-free reaction conditions, to promote the
use of water as reaction media or to develop more en-
vironmentally friendly alternatives. Indeed, the con-
cepts of E-factor and atom economy are steadily
being included in the conventional organic synthesis
[
16]
both in industry as well as academia.
Therefore,
from the standpoint of environmentally benign organ-
ic synthesis, the development of a highly active and
easily reusable immobilized catalysts along with a sol-
vent-free media are of great interest to the chem-
[17]
ists.
The use of graphene and graphene oxide (GO) as
catalysts for various synthetic transformations is a rel-
[
18]
atively a new area with outstanding potential. The
2
À1
high specific surface areas (400 m g
up to
2
À1
1
500 m g ) and thermally stable chemical structures
of GO and chemically derived graphenes (CDG)
make them versatile materials for catalytic applica- Figure 1. XRD pattern of the CuO@GO catalyst prior to
tions either alone or as supports for the catalytically the reaction.
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Copper Oxide Nanoparticles Supported on Graphene Oxide-Catalyzed S-Arylation
Figure 2. TEM images of the CuO@GO catalyst prior to the reaction (a and b), after completion of the reaction (neat, after
rd
th
nd
3
cycle and 5 cycle) (c and d) and in DMSO (after 2 cycle, e).
[
22]
structure due to growth of CuO nanocrystals. Fur- CuO nanoparticles have spherical shape and the sizes
thermore, Figure 2 reveals the TEM images of of the particles observed in TEM images are in the
CuO@GO nanocomposite products. It shows that the range of 40–70 nm (images a and b). The morphology
Adv. Synth. Catal. 2013, 355, 2297 – 2307
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Figure 3. SEM images of the CuO@GO catalyst prior to the reaction (a), after completion of the reaction (b).
[
21]
of the synthesized CuO@GO nanocomposites as seen (Figure 4).
Moreover, the content of CuO in the
in SEM images is displayed in Figure 3, which shows synthesized CuO@GO catalytic system is 5.1 wt%,
that the surfaces of GO sheets are decorated by which was detected by AAS (atomic absorption spec-
spherical CuO nanoparticle aggregates, forming the troscopy) analysis. In addition, the results of nitrogen
CuO@GO nanocomposite. The SEM observations are adsorption experiments illustrate that GO and
consistent with the TEM results. The Raman spec- CuO@GO have BET (Brunauer–Emmett–Teller) sur-
2
À1
trum illustrates the presence of characteristic peaks of face areas of 200.87 and 130.61 m g , respectively.
CuO as well as GO and the positions of the peaks are The initial screening of the reaction has been car-
in complete agreement with the reported values ried out mainly towards the efforts in the develop-
ment of mild reaction conditions for the CÀS cross-
coupling reaction by taking iodobenzene and thiophe-
nol as coupling partners. We have performed this
cross-coupling reaction under different conditions by
varying base, solvent, and temperature in order to de-
termine green and optimal reaction conditions
(
Table 1). Among the conditions screened, the one
where TEA was used as a base without any solvent is
considered to be mild and benign. However, because
of the amphiphilic nature of GO it could be easily dis-
persible in a variety of solvents with different polari-
ties. By utilizing this advantage of GO we have tested
this catalyst activity in a variety of solvents including
water and PEG under different reaction conditions.
Indeed, the reactions of aryl iodide and aryl bromide
are well performed in PEG as a solvent and provided
the required products in good yields. However, in the
case of aryl chloride the observed yield and selectivity
were poor. Besides, water was not suitable for this
conversion and furnished diphenyl disulfide as major
product (Table 1). Moreover, this solventfree CÀS
cross-coupling reaction between iodobenzene and thi-
ophenol in the presence of TEA (2.0 equiv.) afforded
95% yield of the required product with 100% selectiv-
ity in 4.5 h (Table 1, entry 1). We then examined this
coupling reaction between a variety of aryl halides,
Figure 4. Raman spectra of CuO@GO catalyst prior to the heterocyclic halides and various aromatic/aliphatic
reaction (a), after completion of the reaction (b).
thiols which all also proved to be effective coupling
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Copper Oxide Nanoparticles Supported on Graphene Oxide-Catalyzed S-Arylation
Table 1. Screening of reaction conditions by using different bases and solvents for the synthesis of diphenyl sulfide.
Entry
X
Solvent
–
Base
TEA
Time [h]
Yield [%]
Selectivity [1 and 2]
[
a,d]
[d]
[d]
[d]
1
2
3
4
5
6
7
8
9
I
I
I
I
I
I
I
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
4.5, 12.0
3.0
95, 10
100:0, 0:100
[
b]
DMSO[
KOH
95
90
85
20
88
85
80
90
88
60
70
85
85
55
88
100:0
100:0
100:0
0:100
30:70
20:80
95:5
100:0
100:0
95:5
25:75
90:10
90:10
60:40
0:100
b]
DMSO
K CO
3.0
3.0
10.0
9.0
2
3
3
[c]
PEG[
K CO
2
c]
PEG
–
[a]
water[
water
–
KOH
a]
K CO
10.0
13.0
12.0
12.0
12.0
24.0
16.0
16.0
18.0
24.0
2
3
[a]
TEA
KOH
[
b]
DMSO[
b]
10
11
12
13
14
15
16
DMSO
Cs CO
2
3
3
[c]
PEG
–
K CO
2
3
[a]
TEA
KOH
[
b]
DMSO[
b]
DMSO
Cs CO
2
[
c]
PEG
K CO
2
3
[a]
water
KOH
[
a]
Reaction conditions: halobenzene (1.2 mmol), thiophenol (1.0 mmol), base (2.0 mmol), solvent (3 mL), CuO@GO (6 mg,
0.28 mol% vs. halide), 908C.
b]
[
[
[
Reaction at 1108C.
Reaction at 1008C.
No catalyst.
c]
d]
partners. In general, all aryl iodides were coupled Figure 6. After each run, the supported catalyst was
with different types of thiols and offered good selec- recovered by simple filtration and reused directly for
tivity and yield in a considerably smaller amount of the next run of the reaction without further manipula-
time. The catalyst showed good functional group tol- tion. However, the presence of regular peaks of CuO
erance to afford good to excellent yields of the prod- and GO in Raman spectra (Figure 4) as well as XRD
ucts with both activated and non-activated aryl io- (Supporting Information, Figure S1) patterns of used
dides (Table 2, entries 2–10). In addition, it also toler- CuO@GO explained the stability of the catalyst to-
ated aryl halides bearing reducible groups (Table 2, wards the neat reaction conditions. The TEM image
entry 8, 9). Some of the heterocyclic and aliphatic hal- of catalyst after the third cycle showed a small ag-
ides underwent smooth reactions with good yields glomeration of nanoparticles and this agglomeration
under solvent-free conditions (Table 2, entries 11–13, is further increasing upon extended recycling
15). Moreover, especially in the case of 4-iodoaniline (Figure 2, images c and d). Moreover, the AAS analy-
the observed yield is moderate (60%) and it took sis showed that the weight percentage of the reused
longer time to complete the conversion (Table 2, catalyst after five catalytic cycles was 3.9%. However,
entry 10).
a slight loss in the catalytic activity was also observed
The more hydrophobic surface area of the catalyst upon extended recycling, which was not probably
is mainly responsible for its high catalytic activity to- completely due to leaching of the copper oxide nano-
wards various coupling partners as it firmly holds the particles from the support but because slower solubili-
reactants on to its surface and performs the reaction zation of the support resulted in agglomeration of the
faster and easier. The catalyst was separated by nanoparticles over the support. A kinetic analysis plot
simple filtration and products were purified by using for the catalytic activity of CuO@GO towards the CÀ
a flash column chromatography, and the yields were S cross-coupling reaction of iodobenzene and thiophe-
obtained depending on the hydrophobic surface area nol in combination with TEA is illustrated in
of the support. Furthermore, the recovered catalyst Figure 5. In addition, we have calculated the E-factor
was used in six further runs for the S-arylation of value for the CÀS cross-coupling reaction of thiophe-
thio ACHTUNGTRENNUNGp henol with iodobenzene and showed a slowly de- nol with iodobenzene catalyzed by CuO@GO, and ex-
creasing activity upon further reuse as shown in plained the improved greenness of this protocol. The
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[a]
Table 2. CuO@GO-catalyzed S-arylation of various thiols with different aryl halides under solvent free conditions.
1
[d]
[b,d]
[c,d]
Entry
R
R
Time [h]
Yield [%]
Selectivity [1 and 2]
[
e]
e]
e]
[e]
[e]
1
2
3
4
5
6
7
8
9
H
p-CF3
p-Me
m-Me
p-OMe
p-tBu
p-F
p-NO2
m-NO2
p-NH2
2-iodonaphthalene
2-iodonaphthalene
2-iodopyridine
H
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
m-NO -C H
4.5, 13.0[
95, 80
96, 87
94, 75
90
97, 73
90
97, 80
94, 79
88
60
88
95
88
85
91
100:0, 95:5
[e]
[e]
5.0, 14.0[
5.5, 15.0
5.0
100:0, 100:0
[e]
[e]
100:0, 95:5
100:0
[e]
[e]
[e]
5.0, 13.0
5.5
100:0, 90:10
100:0
100:0, 95:5
[e]
[e]
[e]
4.5, 12.5[
e]
[e]
[e]
5.5, 14.0
7.0
9.0
7.0
7.0
8.0
8.5
7.5
100:0, 90:10
100:0
90:10
95:5
100:0
98:2
2
6
4
10
11
12
13
14
15
phenyl
p-Cl-C H
6
4
phenyl
phenyl
butyl
100:0
100:0
iodocyclohexane
p-Me-C H4
6
[
[
[
[
[
a]
Reaction conditions: aryl halide (1.2 mmol), thiol (1.0 mmol), TEA (2 mmol), CuO@GO (6 mg, 0.28 mol% vs. halide).
b]
Isolated yields after column chromatography.
c]
d]
e]
1
Selectivity confirmed by H NMR.
Reaction with iodide.
Reaction with bromide.
Figure 5. Analysis of conversion vs. reaction time for the
catalytic activity of CuO@GO for the CÀS cross coupling re-
Figure 6. Recycling experiments for CÀS cross-coupling of
iodobenzene and thiophenol by CuO@GO. Reaction condi-
tions: [a] iodobenzene (1.2 mmol), thiophenol (1.0 mmol),
TEA (2.0 mmol), CuO@GO (6 mg), 908C; [b] iodobenzene
action of iodobenzene and thiphenol in the presence of
TEA. The conversion was monitored by GC.
(
1.2 mmol), thiophenol (1.0 mmol), KOH (2.0 mmol),
details regarding formula and method of E-factor cal-
culations are depicted in the Supporting Information.
In fact, E-factor analysis substantiates that our pres-
DMSO (3 mL), CuO@GO (6 mg), 1108C.
ent protocol is considerably green and comparable erature for the CÀS cross-coupling reaction (Support-
with some other catalytic systems reported in the lit- ing Information, pages S6–S9).
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Copper Oxide Nanoparticles Supported on Graphene Oxide-Catalyzed S-Arylation
[a]
Table 3. CuO@GO-catalyzed S-arylation of various thiols with different aryl chlorides.
1
[b]
[c]
Entry
R
R
Time [h]
Yield [%]
Selectivity [1 and 2]
1
2
3
4
5
6
7
8
9
H
p-Me
p-F
p-CF3
p-NO2
p-OMe
p-tert-butyl
2-chloronaphthalene
3-chloropyridine
p-Me
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
p-Cl-C H
phenyl
cyclohexyl
16.0
16.5
15.0
15.0
14.0
16.5
17.0
18.0
24.0
24.0
85
83
81
85
86
82
76
78
50
55
90:10
90:10
90:10
95:5
95:5
90:10
90:10
85:15
80:20
85:15
6
4
10
[
a]
Reaction conditions: chlorobenzene (1.2 mmol), thiol (1.0 mmol), Cs CO (2.0 mmol), DMSO (3 mL), CuO@GO (6 mg,
2
3
0
.28 mol% vs. halide).
[
[
b]
Isolated yields after column chromatography.
Selectivity confirmed by H NMR.
c]
1
We have also explored the type of our catalytic conditions (Table 1, entry 12), but it can be successful-
system, which is very important to bring fresh ideas ly used in the presence of DMSO/Cs CO reagent
2
3
[
23]
into modern catalysis.
In order to examine the system. Initially, the reaction was performed with
nature of our catalyst, a hot filtration test was per- chlorobenzene and thiophenol in the presence of
formed for the solvent-free reaction of iodobenzene Cs CO (2.0 equiv.) and CuO@GO (6 mg) in DMSO
2
3
and thiophenol in the presence of TEA. Briefly, after (3 mL), diphenyl sulfide was formed in 85% yield in
achieving about 51% conversion, CuO@GO catalyst 16.0 h (Table 1, entry 14 and Table 3, entry 1). Fur-
was removed from the reaction mixture by hot filtra- thermore, a variety of aryl chlorides with various aro-
tion and the resultant filtrate was allowed to react fur- matic as well as aliphatic thiols in DMSO provided
ther in the absence of solid catalyst. As a significant the corresponding products in good yields and better
improvement in conversion was not observed (only selectivity (Table 3, entries 1–7), except in the case of
55%) after removal of the catalyst, the possibility that heterocyclic aryl chlorides (Table 3, entries 8 and 9).
the reaction was completely promoted by soluble Among the bases used, Cs CO and KOH were found
2
3
CuO species could be ignored. In a complementary to be suitable and reactions were complete in a rela-
approach, the filtrate was also tested by using AAS, tively lesser time as compared with other bases
we found that a very low amount of copper was pres- (Table 1). However, KOH appears to be superior to
ent (only 1% compared with initial copper concentra- Cs CO , but the dissolution of the support was ob-
2
3
tion in the catalyst). Furthermore, the solid catalyst is served more in the case of KOH compared to Cs CO3
2
reused for the next cycle without marginal loss in the upon extended recycling. The TEM image of the cata-
catalytic activity. These experimental results as well as lyst after the second cycle showed a larger agglomera-
TEM and XRD patterns of reused catalyst clearly tion of nanoparticles for the reaction of chloroben-
suggest that the CÀS cross coupling reaction involves zene with thiophenol in the presence of the KOH
a heterogeneous process and the catalysis may occur (2.0 equiv.) and DMSO (3 mL) system as shown in
on the surface of the CuO nanoparticles supported on Figure 2, image e.
GO. Moreover, the dissolution of the support was
In addition, we have demonstrated the scope of ac-
also observed upon extended recycling and it was tivity of this catalyst for the reaction of thiourea with
more in case of DMSO in comparison to solvent-free different aryl halides in order to avoid the use of foul
conditions which resulted in a considerable loss in the smelling thiols. The initial screening has been carried
catalytic activity after three catalytic cycles (Figure 6). out with iodobenzene and thiourea in the presence of
Moreover, this catalytic system is not much favour- Cs CO (2.0 equiv.) and DMSO (4 mL). This pro-
2
3
able in the case of aryl chlorides under solvent-free duced the corresponding symmetrical diphenyl sulfide
Adv. Synth. Catal. 2013, 355, 2297 – 2307
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Ahmed Kamal et al.
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Table 4. CuO@GO-catalyzed reactions of various iodoben-
zenes with thiourea.
Interestingly, this catalytic system is also active for
the synthesis of phenothiazines via the cascade CÀN
and CÀS cross-coupling reaction of aryl ortho-diha-
[a]
lides and ortho-aminobenzothiol. Zeng et al. have re-
ported that the existing shortcomings could be re-
solved if aryl ortho-dihalides and ortho-aminobenzo-
thiols were used as substrates in the synthesis of phe-
[
24]
nothiazines. In this context, we have selected aryl
[
b]
Entry
1
R
Time [h]
Yield [%] ortho-dihalides and ortho-aminobenzothiol as the cou-
[c]
[c]
pling partners for the synthesis of phenothiazine, in
which ortho-diiodobenzene proved to be a better cou-
pling partner over the other two substrates (Table 5).
Firstly, the catalyst system composed of DMSO/
Cs CO afforded the desired product phenothiazine in
H (X=I)
12.0, 12.0
24.0
26.0
13.0
13.5
12.0
11.0
20.0
18.0
98, 32
58
H (X=Br)
H (X=Cl)
p-Me
p-Et
p-CF3
30
96
95
93
95
65
85
75
2
3
4
5
6
7
8
9
2
3
45% yield (Table 5, entry 1) and we also noticed that
the starting materials were consumed totally and an
undesired 2-(2-iodophenylsulfonyl)-phenylamine was
detected to be a predominant by-product. Among the
bases screened, KOH proved to be the better base as
it afforded 60% yield for the coupling of ortho-diio-
dobenzene and ortho-aminobenzothiol (Table 5,
m-NO2
p-NH2
3-iodothiophene
2-iodoindole
2-iodopyrazine
5-iodopyrimidine
20.0
20.0
20.0
83
84
10
[
a]
Reaction conditions: aryl halide (1.0 mmol), thiourea entry 1). Moreover, in case of ortho-dibromobenzene
(
1.5 mmol), Cs CO
(2.0 mmol), DMSO (4 mL),
2
3
the reaction was not effective and almost failed to
achieve the desired product (phenothioazine) in
higher yield, on the other hand the undesired by-
product 2-(2-bromophenylsulfonyl)-phenylamine was
produced.
CuO@GO (10 mg, 0.38 mol% vs. halide).
Isolated yields after column chromatography.
Neat (TEA used as base).
[
[
b]
c]
in 98% yield after 12.0 h (Table 4, entry 1). However,
this reaction was not satisfactory under solvent-free
conditions as the yield was poor (Table 4, entry 1). In Conclusions
particular, all the heterocyclic aryl iodides also react-
ed smoothly and provided the corresponding products In conclusion, we have explored a simple and efficient
in good yields. Moreover, in the case of 4-iodoaniline protocol for solvent- and ligand-free CÀS cross-cou-
the product yield is less (65%) and the time is also pling reactions in the presence of weak bases and rel-
high to complete the conversion (Table 4, entry 6). In atively mild reaction conditions by using the
the case of aryl chloride, the observed yield is less CuO@GO catalytic system. Various CÀS cross-cou-
and there was no improvement in the yield even at pling reactions have been explored by using different
prolonged reaction time (Table 4, entry 1).
bases, and organic/aqueous solvents. Among them,
[a]
Table 5. CuO@GO-catalyzed cascade CÀS and CÀN cross-coupling of aryl ortho-dihalides and ortho-aminobenzothiols.
[b]
Entry
X /X
1
Time [h]
Yield [%]
2
1
2
[c]
[d]
[c]
[d]
1
2
3
I/I
I/Br
Br/Br
13
15
24
60, 45, 10
50
20
40, 50, 50
40
60
[
a]
Reaction conditions: ortho-dihalide (1.1 mmol), ortho-aminobenzothiol (1.0 mmol), KOH (2.0 mmol), DMSO (3 mL),
CuO@GO (10 mg, 0.52 mol% vs. halide).
Isolated yields after column chromatography.
Cs CO used as base.
[
[
[
b]
c]
d]
2
3
Neat (TEA used as base).
2304
asc.wiley-vch.de
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2013, 355, 2297 – 2307

Copper Oxide Nanoparticles Supported on Graphene Oxide-Catalyzed S-Arylation
using TEA as a base the solvent-free synthesis of imately 838C with vigorous stirring for 30 min. Then 5 mL
of deionized (DI) water were rapidly introduced into the
above boiling solution, and the mixture was heated at 838C
diaryl sulfide is considered to be mild and benign.
Furthermore, various aryl chlorides also reacted with
for another 30 min. During this process, the initial brown
corresponding thiols and gave good to excellent yields
colour of the dispersion gradually turned to black. After
in the presence of DMSO/Cs CO . We also explored
2
3
cooling to room temperature, the as synthesized composite
was centrifuged, washed with ethanol several times, and
the scope of this new method for the cross-coupling
reactions between thiourea and aryl iodides for the
synthesis of aryl sulfides. This catalytic system is also
suitable for the synthesis of the phenothiazine ring
system. It is important to note that the E-factor is
[21]
dried at 708C in air overnight.
Typical Procedure for the CuO@GO-Catalyzed CÀS
Cross-Coupling Reaction (Neat)
2.52 and thus is significantly smaller than similar pro-
A
round-bottom flask was charged with aryl halide
tocols reported in the literature. In addition, the
CuO@GO was readily separated by centrifugation
and could be reused six times under the solvent-free
conditions with only a marginal loss of catalytic activi-
ty.
(
1.2 mmol), thiol (1.0 mmol), CuO@GO (6 mg, 0.28 mol%
vs. halide), and Et N (2.0 mmol). This mixture was stirred
3
under N at 908C for the desired time until complete con-
2
sumption of starting materials as monitored by TLC. Upon
completion of the reaction, the mixture was dissolved in
EtOAc and the catalyst was recovered by simple centrifuga-
tion, and reused in the next run. The EtOAc solution was
Experimental Section
washed with water and dried over MgSO , filtered, and con-
4
centrated under vacuum to obtain the crude product. Then,
the residue was purified by flash column chromatography
using hexane alone or hexane/ethyl acetate mixture as
eluent to afford the product with high purity. The organic
solvents used for the purification were recycled under re-
duced pressure and reused successfully. Isolated yields and
General Methods
All chemicals and reagents were used without further purifi-
cation. Reactions were monitored by TLC, performed on
silica gel glass plates containing 60 GF-254, and visualization
on TLC was achieved by UV light or iodine indicator.
Transmission electron microscopy (TEM, operating at 80–
1
purity of the products were confirmed by H NMR.
1
00 kV) was used to investigate the morphology and size of
Typical Procedure for the CuO@GO-Catalyzed CÀS
the nanoparticles. The samples for TEM were prepared by
dispersing the material in water and drop-drying onto
Cross-Coupling Reaction (in DMSO)
a Form
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
var resin coated copper grid. The morphology of the
A round-bottom flask was charged with aryl chloride
(1.2 mmol), thiol (1.0 mmol), CuO@GO (6 mg, 0.28 mol%
vs. halide), Cs CO (2.0 mmol), and DMSO (3 mL). This
samples was determined by using a Model 3400 N Scanning
Electron Microscope. Laser Raman spectroscopy (LRS)
studies were carried out at room temperature. For elemental
analysis, an atomic absorption spectrometer was used. The
BET surface area was determined by N2 gas adsorption
using a Quadrasorb SI System (M/s Quantachrome instru-
ments Corporation, USA) at 77 K by the multi-point
method. Prior to the measurement samples were pre-heated
at 1208C for 1 h in order to expel the interlayer water mole-
2
3
mixture was stirred under N at 1108C for the desired time
2
until complete consumption of starting material as moni-
tored by TLC. Upon completion of the reaction, the mixture
was dissolved in EtOAc and the catalyst was recovered by
simple centrifugation, and reused in the next run. The
EtOAc solution was washed with cold water (2ꢂ10) and
dried over MgSO , filtered, and concentrated under vacuum
4
1
cules. H NMR spectra were recorded on a 300 MHz spec-
to obtain the crude product. Then, the residue was purified
by flash column chromatography using hexane alone or
hexane/ethyl acetate mixture as eluent to afford the product
with high purity. The organic solvents used for the purifica-
tion were recycled under reduced pressure and reused suc-
cessfully. Isolated yields and purity of the products were
13
trometer and
C NMR spectra were recorded on
a 300 MHz spectrometer. Chemical shifts are reported in
parts per million (ppm) downfield from tetramethylsilane as
internal standard. Spin multiplicities are described as s (sin-
glet), bs (broad singlet), d (doublet), dd (double doublet), t
1
(
triplet), q (quartet), or m (multiplet). Coupling constants
confirmed by H NMR.
are reported in hertz (Hz). Flash column chromatography
was performed by using 250–400 mesh silica gel.
Typical Procedure for the CuO@GO-Catalyzed CÀS
Cross-Coupling of Aryl Iodide with Thiourea
Synthesis of GO-Supported CuO Nanoparticle
Catalysts
A
(
round-bottom flask was charged with aryl iodide
1.0 mmol), thiourea (1.5 mmol), CuO@GO (10 mg,
0.38 mol% vs. halide), Cs CO (2.0 mmol), and DMSO
In a typical procedure, GO was synthesized from natural
graphite using a Hummers-Offeman method.
2
3
[25]
The ob-
(4 mL). This mixture was stirred under N at 1108C for the
2
tained crude GO was purified by washing, centrifugation
and was dried at 1208C. Then, 0.05 g of dried GO was sus-
pended in 50 mL of isopropyl alcohol to give a brown dis-
persion by sonicating for 30 min. The resulting homogene-
desired time until complete consumption of starting material
as monitored by TLC. Upon completion of the reaction, the
mixture was dissolved in EtOAc and the catalyst was sepa-
rated by simple filtration. The EtOAc solution was washed
ous dispersion was mixed with 0.14 g of Cu
A
H
U
G
R
N
U
G
with cold water (2ꢂ10) and dried over MgSO , filtered, and
2
2
4
a round-bottomed flask. This mixture was heated to approx-
concentrated under vacuum to obtain the crude product.
Adv. Synth. Catal. 2013, 355, 2297 – 2307
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2305

Ahmed Kamal et al.
FULL PAPERS
Then, the residue was purified by flash column chromatog-
raphy using hexane alone or hexane/ethyl acetate mixture as
eluent to afford the product with high purity. The organic
solvents used for the purification were recycled under re-
duced pressure and reused successfully. Isolated yields and
G. Chiosis, A. Brancale, E. Hamel, M. Artico, R. Sil-
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Typical Procedure for the CuO@GO-Catalyzed
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2
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[
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4
1
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column chromatography using hexane alone or hexane/ethyl
acetate mixture as eluent to afford the product with high
purity. The organic solvents used for the purification were
recycled under reduced pressure and reused successfully.
Isolated yields and purity of the products were confirmed by
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7
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Reusability Study of the Catalyst
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after sufficient washing with ethanol and subsequent dry-
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1
V.S., J.N.S.R.C.M., T.S.R. and A.V.S.R. are thankful to CSIR,
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