Room temperature Ullmann type C-O and C-S cross coupling of aryl halides with phenol/thiophenol catalyzed by CuO nanoparticles

Article abstract of DOI:10.1016/j.tetlet.2013.01.063

C-O/C-S cross coupling of aryl halides with phenol or thiophenol was studied under ligand-free condition at room temperature over CuO nanocatalyst. The scope of the reaction was extended to various aryl halides and substituted phenols under optimized condition. In general, efficient, selective, and reusable heterogeneous nano CuO catalytic system has been developed for room temperature C-O and C-S Ullmann type cross coupling reactions.

Full text of DOI:10.1016/j.tetlet.2013.01.063

Tetrahedron Letters 54 (2013) 1677–1680
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Room temperature Ullmann type C–O and C–S cross coupling of aryl
halides with phenol/thiophenol catalyzed by CuO nanoparticles
⇑
S. Ganesh Babu, R. Karvembu
Department of Chemistry, National Institute of Technology, Tiruchirappalli 620 015, India
a r t i c l e i n f o
a b s t r a c t
Article history:
C–O/C–S cross coupling of aryl halides with phenol or thiophenol was studied under ligand-free condition
at room temperature over CuO nanocatalyst. The scope of the reaction was extended to various aryl
halides and substituted phenols under optimized condition. In general, efficient, selective, and reusable
heterogeneous nano CuO catalytic system has been developed for room temperature C–O and C–S Ull-
mann type cross coupling reactions.
Received 27 October 2012
Revised 11 January 2013
Accepted 13 January 2013
Available online 23 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Ullmann type cross coupling
Phenol
Thiophenol
Aryl halide
CuO nanocatalyst
Diaryl ethers and diaryl thioethers syntheses have absorbed
more attention in recent years because it is found in subunits of
many synthetically challenging and medicinally important natural
use of heterocyclic substrates and ortho-substituted coupling part-
1
2
ners in intermolecular reactions is rare. Furthermore, the com-
mercially available boronic acids are expensive. For the past two
decades nanoparticles have found much importance in catalysis
because of its high surface area and high activity. Sreedhar et al.,
used copper iodide nanoparticles for the C–O cross coupling of
1
products. Most diaryl ethers in nature originate from the aromatic
2
amino acids (pulcherosine, isodityrosine, etc.). Thyroxin is the ma-
jor hormone secreted by the follicular cells of the thyroid gland and
was among the first diaryl ethers detected in nature and prepared
1
3
phenols with chlorobenzenes at 110 °C. Magnetic CuFe
2 4
O nano-
3
in the laboratory. S-substituted 4-methyl-7-mercaptocoumarins
particles-catalyzed Ullmann type ether synthesis was carried out
1
4
are found to be the most potent cytotoxic analogs for pharmaco-
at 135 °C. Metallic copper nanoparticles have been used for O-
4
15
logical studies in the A549 human lung cancer cell line (Fig. 1).
arylation of phenols with aryl halides at 60 °C. Park and co-work-
Traditionally, diaryl ethers and diaryl thioethers were synthesized
via a nucleophilic aromatic substitution or transition metal-cata-
lyzed Ullmann type and Hartwig and co-workers6 or Buchwald-
5
H2N
COOH
7
type O-arylation and S-arylation reactions. Smith and co-workers,
OH
reported an alternative synthesis procedure for Ullmann type cou-
pling using potassium fluoride on alumina and 18-crown-6 as cat-
alyst under refluxing condition.8 Zhao and Wang, synthesized
diaryl ethers via coupling of aryl halides with substituted phenoxy-
trimethylsilane in the presence of tetra-n-butylammonium fluo-
O
HO
OH
NH2
HOOC
COOH
HOOC
NH2
O
9
NH2
ride at 100 °C. Organic–inorganic hybrid solids with copper
HOOC
NH2
complex framework have also been employed as an effective cata-
lyst for the S-arylation of thiophenol.10 In an important advance,
(a) Pulcherosine
(b) Isodityrosine
copper-catalyzed coupling of boronic acid with phenols have been
developed under mild conditions.11 Though this method possesses
a number of advantages, some limitations remain. An excess of
boronic acid component is required for optimal yields and the
I
O
I
NH2
(
HOOC
I
OH
Cl
N
S
O
O
I
(
d) S-substituted 4-methyl-
-mercaptocoumarins
c) L-Thyroxin
7
⇑
Corresponding author. Tel.: +91 431 2503636; fax: +91 431 2500133.
E-mail address: kar@nitt.edu (R. Karvembu).
Figure 1. Pharmaceutically active C–O/C–S coupled structures.
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.063

1
678
S. G. Babu, R. Karvembu / Tetrahedron Letters 54 (2013) 1677–1680
Table 1
C–O and C–S cross coupling of aryl halides with phenol/thiophenol
a
Optimization of reaction conditions
at room temperature. Previous literatures are available for CuO
nanoparticles-catalyzed Ullmann type coupling. Zhang et al., re-
ported nano CuO-catalyzed Ullmann coupling of phenols with aryl
Entry Solvent
Base
Catalyst amount (mol %) Isolated yield (%)
1
2
3
4
5
6
7
8
9
0
1
2
DMF
DMAc
KOH
KOH
Toluene KOH
3
3
3
3
3
3
3
3
79
90
3
41
1
24
halides under ligand-free condition in DMSO solvent at 110 °C.
Jammi et al., demonstrated CuO nanoparticles-catalyzed C–N, C–
DMSO
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
KOH
WOB
O, and C–S cross coupling reactions in DMSO solvent at 80–
25
1
10 °C. The reaction was performed at elevated temperature in
K
3
PO
(CH
CO
4
2
both the above said catalytic systems. In the former case, CuO
3
)
3
COK
42
Trace
8
13
24
20
K
2
3
nanoparticles (30–40 nm) were prepared from Cu(NO O.
3
)
ÁH
2 2
KOH
KOH
KOH
KOH
0
Commercially available CuO nanoparticles (33 nm) have been used
in the latter case. But in our protocol, CuO nanoparticles with 6–
1
1
1
1.5
4.5
6
2
6
8
nm size have been prepared from Cu(CH
3
COO)
2
ÁH
2
O. This helps
us to develop a catalytic system for Ullmann type cross coupling at
room temperature.
Bold text indicates optimized condition.
a
Reaction conditions: phenol (1.2 mmol), 4-bromobenzonitrile (1 mmol), KOH
The crystallinity of the nano-CuO was examined by powder X-
ray diffraction. The powder XRD peaks correspond to monoclinic
crystal system. The particle size of the formed CuO nanoparticles
was found to be 8 nm (calculated using Scherrer’s equation). TEM
images revealed that the particle size is less than 10 nm which is
in good agreement with the calculation made by Scherrer’s equa-
(
2 mmol), and CuO nanoparticles in 4 mL of solvent, 27 °C.
ers, used Cu
1
2
O nanocube for the same coupling reaction at
50 °C. Very recently, nanoferrite-DOPA-copper catalyst has been
1
6
disclosed for the coupling of thiophenols with aryl halides at
1
17
tion. The BET surface area of CuO nanoparticles was found to be
20 °C under microwave irradiation. All the above said reactions
2
8
1 m /g. Thermal stability of the catalyst was found with TG anal-
were carried out at an elevated temperature. To the best of our
knowledge, this is the first room temperature Ullmann type cross
coupling of aryl halides with phenols/thiophenols.
Copper based nanoparticles have been utilized as catalysts in
various carbon–carbon and carbon–hetero atom bond formation
ysis and found to be stable up to 927 °C.
In order to optimize the reaction conditions such as solvent,
base, catalyst amount, and reaction time, the coupling of phenol
with 4-bromobenzonitrile was used as a model system. Among
the four solvents tested (Table 1, entries 1–4), DMAc produced
1
8
reactions. CuO nanoparticles have been employed as an effective
catalyst for organic synthesis such as coupling of diaryl diselenide
9
0% coupled product and hence it has been used for further inves-
1
9
tigations. The reaction was carried out with different bases and the
results are given in Table 1 (entries 2, 6–8). Potassium hydroxide
(2 mmol) was found to be an effective base for the present coupling
reaction. Only a trace amount of product was formed when the
with aryl halides, CÀN cross coupling of amines with iodoben-
2
0
21
zene,
azole,
C-arylation of b-diketones,
N-arylation of benzimid-
2
2
23
S-arylation of thiophenol at 80 °C,
etc. We report
herein CuO nanoparticles as a ligand-free catalyst for Ullmann type
Table 2
a
CuO-catalyzed O-arylation of phenol
R2
R3
R2
R3
OH
X
O
CuO nanoparticles (3 mol%)
KOH, DMAc
R1
R4
R1
R4
o
2
7 C
Entry
12
R1
R2
X
R3
R4
Reaction time (h)
Isolated yield (%)
4
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
NO
NO
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
Cl
Br
Br
H
H
H
H
H
H
H
H
H
H
H
CN
CHO
H
H
H
CN
CN
24
20
24
22
18
22
24
24
28
28
16
24
24
24
24
22
28
28
24
24
24
87
81
79
77
76
82
89
86
79
71
92
61
60
72
65
69
73
67
80
57
54
2
9
9
1
1
4
2
3
4
5
6
7
8
9
CHO
CHO
COCH
COCH
CF
CF
CH
OCH
NO
H
4
4
3
3
3
3
14
3
1
1
1
1
1
1
1
1
1
1
2
2
01
4
3
14
1
2
2
3
4
5
6
7
8
9
0
1
H
H
CN
2
8
NO
NO
NO
NO
NO
NO
H
2
2
2
2
2
2
CHO
COCH
CF
OCH
NO
CN
H
3
H
H
H
H
3
3
28
2
2
2
H
CHO
a
Reaction conditions: phenol/substituted phenol (1.2 mmol), aryl halide (1 mmol), KOH (2 mmol, 112 mg), and CuO nanoparticles (3 mol %, 10 mg) in 4 mL of DMAc, 27 °C.

S. G. Babu, R. Karvembu / Tetrahedron Letters 54 (2013) 1677–1680
1679
Table 3
7 and 8; the leaving group ability of halogens are in the order of
I > Br > Cl > F). Even then, the aryl chlorides with p-electron with-
drawing groups are also coupled with phenol to afford the corre-
sponding O-arylated products in excellent yields (Table 2, entries
2, 4, 6, 8, 10, 11, and 19). This clearly reveals the efficiency of the
present catalytic system. As the electron withdrawing effect of
the substituent at the phenyl ring of aryl halide increases, the reac-
tivity toward O-arylation increases. Since, nitro group is one of the
strongest electron withdrawing groups, it gives better yield (92%,
Table 2, entry 11) as compared to other substrates. Whereas the
a
CuO-catalyzed S-arylation of thiophenol
SH
X
S
CuO nanoparticles (3 mol%)
R1
R2
KOH, DMAc
R1
R2
o
2
7
C
Entry
R1
X
R2
Reaction time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Cl
CN
CN
10
12
18
20
15
18
15
15
8
92
89
85
87
81
79
93
87
95
CHO
CHO
2
electron withdrawing substituent (–NO ) present in the phenolic
ring decreases the nucleophilicity of the oxygen atom, and hence
lowers the reactivity (Table 2, entries 12–17). The reaction of aryl
halides having electron releasing substituent gave lower yield as
compared to aryl halides having electron withdrawing substituent
(Table 2, entries 9, 10, and 18). The present catalytic system can be
extended to ortho aryl halides (Table 2, entries 12 and 13) and
ortho substituted phenol (Table 2, entries 20 and 21). As expected,
the yields were comparatively lower which may be due to the ste-
ric hindrance associated with the ortho substituent.
COCH
COCH
3
3
CF
CF
3
3
29
9
NO
2
a
Reaction conditions: thiophenol (1.2 mmol), aryl halide (1 mmol), KOH
2 mmol, 112 mg), and CuO nanoparticles (3 mol %, 10 mg) in 4 mL of DMAc, 27 °C.
(
To explore the reactivity of thiophenol, it was reacted with var-
ious aryl halides (Table 3). As the nucleophilicity of mercapto
group is higher, thiophenol reacts faster than phenol, which re-
flects in the low overall reaction time. The C–S cross coupling of
thiophenol and aryl halide follows the same substituent effect as
in C–O coupling.
XH
Br
N
CuO nanoparticles (3 mol%)
KOH, DMAc
X
N
Y
Y
2
7 o
C
X = O; Y = C; Isolated Yield = 84%
X = S; Y = C; Isolated Yield = 89%
X = O; Y = N; Isolated Yield = 85%
X = S; Y = N; Isolated Yield = 92%
The C–O/C–S cross coupling of phenol/thiophenol was also
tested with heterocyclic bromides (Scheme 1). The reactions pro-
ceeded well with both 2-bromopyridine and 2-bromopyrimidine.
The yields were ranging from 84% to 92%.
2
9
Scheme 1. C–O/C–S cross coupling of phenol/thiophenol with 2-bromopyridine/2-
bromopyrimidine.
Regioselectivity test was performed with phenol and 1-bromo-
4-chlorobenzene (Scheme 2). Selectively (100%) 1-chloro-4-phen-
oxybenzene was formed in 72% yield. Thus, this method can be
easily adopted for the regioselective coupling of phenolic –OH with
bromo group in the presence of chloro group. To study the che-
moselectivity, a mixture of phenol and thiophenol was stirred with
reaction was carried out without base (Table 1, entry 5). The cou-
pling reaction proceeds smoothly with 3 mol % of catalyst to give
4
-phenoxybenzonitrile in good yield (Table 1, entry 2). Cross cou-
pling of phenol with 4-bromobenzonitrile was monitored at 0, 3, 6,
2, 18, 24, and 36 h time intervals and the yield of 4-pheno-
xybenzonitrile was found to be 0%, 6%, 23%, 48%, 80%, 90%, and
8%, respectively. These results showed that the yield of the prod-
uct increases significantly while increasing the reaction time from
4
-bromobenzonitrile in the presence of 3 mol % of catalyst. Thio-
phenol couples more readily with 4-bromobenzonitrile to form
-(phenylthio)benzonitrile with the yield of 92% compared to phe-
1
4
nol which gave only 8% of 4-phenoxybenzonitrile (Scheme 3). This
chemoselectivity may be explained by means of the difference in
9
the acidity of –OH and –SH protons. The pK
thiophenol is 9.95 and 8.20, respectively. If the value of pK
a
value of phenol and
is lar-
0
2
to 24 h and after another 12 h, increase in yield is meager. So,
4 h was noted as the optimum reaction time.
a
ger, the extent of dissociation will be smaller. So thiophenol disso-
ciates more easily than phenol and hence reacts faster with 4-
bromobenzonitrile. This study clearly reveals that this method
can be applied to chemoselective S-arylation in the presence of
phenolic –OH.
Scope of the present catalytic system was extended to various
aryl halides and phenols (Table 2).27 The yield is ranging from
5
4% to 92%. The yield is comparable with already reported catalytic
18–20
systems for O-arylation of phenol.
As expected, aryl bromides
gave comparatively good yield than aryl chlorides (Table 2, entries
CuO nanoparticles
OH
SH
Br
(3 mol %)
O
S
CN
KOH, DMAc
2
CN
CN
7 oC, 24 h
GC Yield 8%
GC Yield 92%
Scheme 2. Regioselective O-arylation of phenol.
CuO nanoparticles
(
3 mol %)
O
O
OH
Br
KOH, DMAc
Cl
Br
Cl
o
2
7
C, 24 h
Selectivity 100%
GC Yield 72%
Selectivity 0%
Scheme 3. Chemoselective S-arylation of thiophenol in the presence of phenol.

1
680
S. G. Babu, R. Karvembu / Tetrahedron Letters 54 (2013) 1677–1680
6. Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67,
To explore the reusability of CuO nanoparticles, the coupling of
5553–5566.
phenol with 4-bromobenzonitrile was chosen as a model reaction.
The catalyst could be reused four times without much decrease in
the yield of the product. For the first three cycles, the yield of 4-
phenoxybenzonitrile was found to be 90% and for the fourth run
it was 89%. This result clearly reveals the heterogeneous nature
of the catalyst. In each cycle, the catalyst was recovered, washed
with ethylacetate (3 Â 5 mL) and then dried under reduced pres-
sure. The recovered catalyst was reused for the next cycle.
In conclusion, simple, efficient, regio- and chemoselective, reus-
able, and heterogeneous nano CuO-catalyzed Ullmann type C–O/C–
S cross coupling of aryl halide with phenol/thiophenol has been
demonstrated at room temperature. The reaction conditions were
optimized and the scope was explored with various aryl halides
and phenol/substituted phenol/thiophenol.
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Acknowledgment
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Supplementary data
5
2
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Supplementary data (detailed procedure for catalyst prepara-
tion and characterization of catalyst and catalytic products) associ-
ated with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2013.01.063.
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7. Procedure for C–O/C–S cross coupling: A magnetic stirring bar, nanocrystalline
CuO (10 mg, 3 mol %), KOH (112 mg, 2 mmol) and phenol/substituted phenol/
thiophenol (1.2 mmol) were added into an oven-dried flask (25 mL). The flask
was sealed with a septum, followed by three cycles of evacuation and filling
with dry nitrogen. Then aryl halide (1 mmol) and N,N-dimethyl acetamide
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