An efficient arylation of benzoazoles with aryl bromides by a practical palladium-copper cocatalytic system

Article abstract of DOI:10.3987/COM-11-12176

A practical, efficient Pd(OAc)₂/Cu(II)/PPh₃ cocatalytic system has been developed. With only 1 mol% Pd(OAc)₂, 20 mol% copper(II) salt, and 0.5 equiv of inexpensive PPh₃ as ligand, the direct arylation of benzoazoles with aryl bromides could be performed smoothly in mild condition, affording the desired arylated benzoazoles in good yields (75-93%).

Full text of DOI:10.3987/COM-11-12176

HETEROCYCLES, Vol. 83, No. 6, 2011
1371
HETEROCYCLES, Vol. 83, No. 6, 2011, pp. 1371 - 1376. © The Japan Institute of Heterocyclic Chemistry
Received, 15th February, 2011, Accepted, 28th March, 2011, Published online, 14th April, 2011
DOI: 10.3987/COM-11-12176
AN EFFICIENT ARYLATION OF BENZOAZOLES WITH ARYL
BROMIDES BY A PRACTICAL PALLADIUM-COPPER COCATALYTIC
SYSTEM
Xue-Ming Yan,a,c Xue-Rong Mao,a and Zhi-Zhen Huang*a,b
aSchool of Chemistry and Chemical Engineering, Nanjing University, Nanjing
b
210093, P. R. China, Department of Chemistry, Zhejiang University, Hangzhou
c
310028, P. R. China, College of Chemistry and Chemical Engineering,
University of South China , Hengyang, Hunan 421001, P. R. China
Abstract – A practical, efficient Pd(OAc)2/Cu(II)/PPh3 cocatalytic system has
been developed. With only 1 mol% Pd(OAc)2, 20 mol% copper(II) salt, and 0.5
equiv of inexpensive PPh3 as ligand, the direct arylation of benzoazoles with aryl
bromides could be performed smoothly in mild condition, affording the desired
arylated benzoazoles in good yields (75-93%).
Arylated azoles are ubiquitous in natural products and pharmaceuticals, agrochemicals.1 The
transition-metal catalyzed direct arylation of azoles is a powerful strategy for the synthesis of arylated
azoles, and has recently received much attentions.2 In this rapidly growing field, the direct cross-coupling
between azoles and aryl halides is a main protocol.2 As one of the most common arylated azoles, arylated
benzoazoles have many biologically important activities.3 In most cases, the direct arylation of
benzoazoles catalyzed by transition-metal required more reactive aryl iodides as arylating reagents.2b-d
The direct arylation of benzoazoles using aryl bromides, which are cheaper and more commonly used
than aryl iodides, did not studied so widely as that using aryl iodides.4,5 In 2005, Alagille et al disclosed a
Pd(OAc)2/Cu(I)Br/P(t-Bu)3 cocatalytic system for the direct arylation of benzoazoles with aryl bromides,
affording arylated benzoazoles in 8-84% yields.5a Very recently, Huang et al5b developed an arylation of
benzoazoles with aryl bromides by a palladium-copper cocatalytic system, which employed a complicated
cocatalytic system: dichlorobis(chloro-di-tert-butylphosphine)/Cu(Xantphos)I. Herein we wish to report
our recent work on the efficient arylation of benzoazoles with aryl bromides by a practical
Pd(OAc)2/Cu(II)/PPh3 cocatalytic system.

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HETEROCYCLES, Vol. 83, No. 6, 2011
The direct coupling of benzoxazole 1a with bromobenzene 2a using K2CO3 as a base in toluene was
chosen as a model reaction. Initially, various copper salts and Pd(OAc)2 with various N- and P-ligands
were probed. It was found that N-ligands such as 1,10-phenanthroline or 2,2-bipyridine led to no desired
coupling product (Table 1, entry 1). To our delight, when the inexpensive PPh3 was used, the coupling
reaction performed smoothly with only. 1 mol% Pd(OAc)2 and 20 mol% copper (II) salt such as
.
.
Cu(OAc)2 H2O and CuCl2 2H2O under air, affording the desired arylated benzoxazole 3a in good yields
(Table 1, entries 2 and 3). In the presence of other P-ligands such as (n-Bu)3P and
bisdiphenylphosphinopropane (DPPP), good yields were also obtained (Table 1, entries 5-8). In contrast,
no reaction proceeded in the absence of P-ligands (Table 1, entry 9). The screening of bases revealed that
K2CO3 was much better than other bases for the reaction (Table 1, entries 10-12). Other palladium
catalyst such as PdCl2, Pd(PPh3)4, Pd(PPh3)2Cl2, and Pd(dba)2 with copper (II) salts can also give the
desired product 3a in good yields (Table 1, entries 13-17). Notably, if either copper or palladium catalyst
was present, no arylated product 3a was obtained under the above standard conditions (Table 1, entries 18,
19).
Table 1. Optimization of Direct Arylation of Benzoxazolea
N
O
Palladium/Copper(II) salt
K CO , ligand
N
+
Br
O
2
3
toluene, reflux
3a
1a
2a
Entry
1
2
3
4
5
6
7
Copper
Palladium
Ligand
Yieldb
0
Cu(II) saltc
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Palladium catalystg
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
N-ligandsd
PPh3
.
CuCl2 2H2O
90
92
0
88
85
87
89
0
.
Cu(OAc)2 H2O
PPh3
PPh3
(n-Bu)3P
(n-Bu)3P
DPPP
DPPP
-
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
Cu(acac)2
.
CuCl2 2H2O
.
Cu(OAc)2 H2O
.
CuCl2 2H2O
.
8
9
Cu(OAc)2 H2O
Cu(II) saltc
10e
11e
12f
13
14
15
16
17
18
19
CuCl2 2H2O
0
.
.
Cu(OAc)2 H2O
80
70
90
87
90
92
86
0
.
CuCl2.2H2O
CuCl2 2H2O
.
Cu(OAc)2.H2O
PdCl2
Cu(OAc)2.H2O
Cu(OAc)2.H2O
Cu(OAc)2 H2O
Cu(II) saltc
-
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd(dba)2
-
PdXg
0
aThe mixture of 1a (1.0 mmol), 2a (1.2 mmol), palladium catalyst (1.0 mol%), copper catalyst (20 mol%),
b
ligand (0.5 equiv), and K2CO3 (2.0 equiv) in toluene(3 mL) was refluxed for 3h under air. Isolated
.
.
yields(%). cCu(II) salt: Cu(OAc)2 H2O , CuCl2 2H2O et al dN-ligands =1,10-phenanthroline or
e
f
.
g
2,2-bipyridine. Cs2CO3 was used as base. K3PO4 3H2O was used as base. Palladium catalysts listed in
the table.

HETEROCYCLES, Vol. 83, No. 6, 2011
1373
After screening of various copper and palladium catalysts, ligands, bases etc, it can be concluded that the
optimized reaction should be performed by the cocatalytic system of 1 mol% Pd(OAc)2 and 20 mol%
.
.
Cu(OAc)2 H2O or CuCl2 2H2O in the presence of PPh3 (0.5 equiv) and K2CO3 (2.0 equiv). Under the
optimal reaction conditions, a series of aryl bromides 2a-l were examined in the coupling reaction. It was
found that the aryl bromides bearing either electron-donating or withdrawing groups on benzene rings
2a-i could perform the coupling reaction smootly with benzoxazole 1a under air, furnishing the desired
arylated benzoxazole 3a-i in good yields (Table 2, compare entries 1-10). Heteroaryl bromides 2k-l were
also good coupling partners, giving the biheteroarenes 3k-l in good yields (Table 2, entries 11, 12).
Table 2. Direct Arylation of Benzoxazole 1a with Aryl Bromides 2a
N
O
Pd(OAc) /Cu(II) salt
2
N
O
Ar Br
+
Ar
PPh , K CO
3
3
2
toluene, reflux
1a
2
3
Entry
Ar
Product 3b
Yield (%)c
Yield (%)d
1
2
C6H5
3a7a
3b7b
3c7b
3d7c
3e7c
3f7b
3g7b
3h7a
3i7a
93
88
90
92
84
91
81
83
87
83
92
91
89
86
89
88
80
82
83
85
4-MeOC6H4
3-MeOC6H4
4-MeC6H4
3
4
5
3-MeC6H4
6
3,5-Me2C6H3
2-MeOC6H4
4-FC6H4
7
8
9
4-ClC6H4
10
naphthalen-1-yl
pyridin-3-yl
pyridin-2-yl
3j7b
11
12
3k7b
3l7b
80
80
84
77
aThe mixture of 1a (1.0 mmol), 2 (1.2 mmol), Pd(OAc)2 (1.0 mol%), copper (II) salt (20
mol%), PPh3 (0.5 equiv), and K2CO3. (2.0 equiv) in toluene (3 mL) was refluxed for 3 h
.
under air. bIsolated yields. cCu(OAc)2 H2O was used as cocatalyst. dCuCl2 2H2O was used
as cocatalyst.
Table 3. Direct Arylation of Benzothiazoles 1b or Benzoimidazoles 1c with Aryl Bromides 2a
N
.
N
X
Pd(OAc) /Cu(OAc) H O
2
2
2
Ar Br
+
Ar
X
K CO , PPh
3
2
3
toluene, reflux
1b, X=S
1c, X=NCH3
4, X=S
5, X=NCH3
2

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HETEROCYCLES, Vol. 83, No. 6, 2011
Product
Ar
Yield (%)b
Product
Ar
Yield (%)b
4a5b
4b4c
4c4c
4d5b
4e5b
4f5b
4g5b
4h4c
C6H5
86
92
83
84
82
92
81
77
4i4c
5a7b
5b7a
5c7b
5d7a
5e7a
5f7a
-
pyridin-3-yl
C6H5
79
80
85
81
83
77c
75
-
4-MeOC6H4
3-MeOC6H4
4-MeC6H4
4-MeOC6H4
3-MeOC6H4
4-MeC6H4
3-MeC6H4
3,5-Me2C6H3
-
3-MeC6H4
3,5-Me2C6H3
4-FC6H4
naphthalen-1-yl
.
aThe mixture of 1b or 1c (1.0 mmol), 2 (1.2 mmol), Pd(OAc)2 (1.0 mol%), Cu(OAc)2 H2O (20 mol%),
PPh3 (0.5 equiv), and K2CO3 (2.0 equiv) in toluene (3 mL) was refluxed for 1b 6 h or for 1c 10 h.
.
bIsolated yields. cCuCl2 2H2O was used as cocatalyst.
Moreover, benzothiazole 1b and benzoimidazole 1c were also tested in the coupling reaction using
.
Pd(OAc)2/Cu(OAc)2 H2O/PPh3 as a cocatalytic system. It was found that both benzothiazole 1b and
benzoimidazole 1c could react smoothly with various aryl bromides 2 to give the desired arylated
products 4 and 5 in moderate to good yields (Table 3). Compared with benzoxazole 1a, benzothiazole 1b
and benzoimidazole 1c were less reactive and required longer reaction time (3 h for 1a, 6 h for 1b and
10h for 1c), probably because the acidities of H-2 in 1b and 1c are weaker than that in 1a.6
In summary, a practical Pd(OAc)2/Cu(II)/PPh3 cocatalytic system has been developed for the direct
arylation of benzoazoles 1a, benzothiazole 1b or benzoimidazole 1c with various aryl bromides 2. The
5a
yields (75-93%) are better than that using Pd(OAc)2/Cu(I)Br/ P(t-Bu)3. This synthetic reaction also has
the advantages of readily available catalysts, low palladium catalyst loading, mild reaction conditions,
and simple manipulations.
EXPERIMENTAL
General procedure for the arylation of benzoazoles 1a-c with aryl bromide 2: The reaction mixture of
.
benzoazoles 1a-c (1.0 mmol), aryl bromide 2 (1.2 mmol), Pd(OAc)2 (2.2 mg, 1.0 mol%), Cu(OAc)2 H2O
.
or CuCl2 2H2O (20 mol%), and K2CO3 (2.0 equiv, 0.276 g) in toluene (3 mL) was refluxed for 3-10 h.
Then, the mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was
purified by column chromatography (silica gel, petroleum ether/ EtOAc as eluent) to give arylated
benzoxazole 3-5
4a5b,b4c,c4c,d5b,e5b,f5b,g5b,h4c,i4c; 5a7b,b7a,c7b,d7a,e7a,f7a are known compounds ).
(All the coupling products 3a7a,b7b,c7b,d7c,e7c,f7b,g7b,h7a,i7a,j7b,k7b,l7b;

HETEROCYCLES, Vol. 83, No. 6, 2011
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ACKNOWLEDGEMENTS
Financial supports from National Natural Science Foundation of China (No. 20872059 and 21072091)
and MOST of China (973 program 2011CB808600) are gratefully acknowledged.
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