Copper and iron-assisted palladium-catalyzed direct arylation of azoles with arylboronic acids under ligand and base-free conditions

Article abstract of DOI:10.2174/15701786113109990034

The direct arylation of azoles with arylboronic acids is effectively promoted by PdCl₂ in the presence of copper and iron salts under ligand and base-free conditions. This reaction can be applied to heterocycles such as benzothiazole, benzoxazole, 1-methylbenzimidazole and 4,5-dimethylthiazole with moderate to good yields.

Full text of DOI:10.2174/15701786113109990034

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668
Letters in Organic Chemistry, 2013, 10, 668-673
Copper and Iron-assisted Palladium-catalyzed Direct Arylation of Azoles
with Arylboronic Acids under Ligand and Base-free Conditions
Xiang-Mei Wu* and Qiu-Xian Shen
Department of Chemistry, College of Science, Lishui University, Lishui, Zhejiang 323000, China
Received May 28, 2013: Revised July 10, 2013: Accepted July 10, 2013
Abstract: The direct arylation of azoles with arylboronic acids is effectively promoted by PdCl2 in the presence of copper
and iron salts under ligand and base-free conditions. This reaction can be applied to heterocycles such as benzothiazole,
benzoxazole, 1-methylbenzimidazole and 4,5-dimethylthiazole with moderate to good yields.
Keywords: Palladium, copper, iron, arylation, arylboronic acid.
INTRODUCTION
RESULTS AND DISCUSSION
Aryl-azoles such as aryl-substituted benzothiazoles, ben-
zoxazoles and benzimidazoles represent a predominant struc-
tural motifs in a wide array of biologically important natural
products and synthetic pharmaceuticals [1]. Moreover, they
have also found applications in organic functional materials
like fluorescent dyes and liquid crystals [2]. Therefore, the
development of efficient synthesis of aryl-substituted azoles
and their derivatives have stimulated consideration interest.
The typical approaches to prepare these important com-
pounds involve either the metal-catalyzed intramolecular
cyclization of thioanilides (or 2-haloanilides) or the conden-
sation of 2-aminophenol (or 2-aminothiophenol) with car-
boxylic acid derivatives or aldehydes [3]. As a variety of
transition metal-mediated C-C bond formations through
aromatic C-H activation directly have received significant
attention owing to its advantage in atom efficiency compared
to traditional cross-couplings [4], aryl-substituted azoles
prepared by direct arylation of heterocycles through metal-
catalyzed C-H bond activation with aryl halides [5], aromatic
carboxylic acids [6], arylsilanes [7], aldehydes [8], and so-
dium arylsulfinates [9] have also attracted attention recently.
In addition, a few successful examples of the coupling of
azoles with arylboronic acids have also been described so far
[10-13], however, these protocols generally require the
stoichiometric amount of base which may facilitate the ho-
mocoupling of arylboronic acid and organic ligands or addi-
tives which make it difficult for the separation and purifica-
tion after the reactions. Consequently, considering the pref-
erence of modern green chemistry, the development of an
efficient ligand and base-free reaction system is still highly
desirable. Herein, we describe a simple and practical syn-
thetic pathway to achieve the direct C-H bond functionaliza-
tion of benzothiazole, benzoxazole, 1-methylbenzimidazole
and 4,5-dimethylthiazole with arylboronic acids by transi-
tion-metal catalysts under ligand and base-free conditions.
We undertook an intensive screening process using ben-
zothiazole and phenylboronic acid as model substrates. Ac-
cording to the literature [10-13], the reaction conditions may
require an oxidant to regenerate the Pd catalyst, so Cu(OAc)2
was initially used to play as the role in the model reaction. In
the presence of 10 mol% of Pd(OAc)2 as the catalyst and 1
equiv of Cu(OAc)2 as the oxidant in DMSO at 120°C for
24h, to our delight, 2-phenylbenzothiazole was isolated in
30% yield (Table 1, entry 1). At the same time, substantial
amount of biphenyl resulted from consumption of phenylbo-
ronic acid and small amount of bibenzothiazole resulted
from the undesired homocoupling of benzothiazole were
determined by gas chromatography. As the palladium
sources, the comparable product yields were obtained when
PdCl2 and Pd(MeCN)2Cl2 were used as the catalyst whereas
a lower yield was afforded when Pd/C was used instead of
Pd(OAc)2 (entries 2-4). In the absence of Pd, a majority of
benzothiazole were recovered from the reaction system and a
small amount of unexpected product through ring-opening
arylation (2-aminophenyl sulfide) was detected (entry 5). So
PdCl2 was chosen as catalyst in the following investigation
due to its low cost. Various Cu(II) salts, such as CuSO4,
CuCl2 and CuO were also examined as oxidants for this di-
rect arylation reaction, and Cu(OAc)2 was the best choice
obviously (entries 6-8). However, other oxidants like K2S2O8
and (NH4)2S2O8 were no longer effective in the reaction (en-
try 9).
Then the effect of additive on this reaction was also in-
vestigated to improve our low reaction yield. Inspired by
results reported by Georg et al. that the addition of CuCl2
can effectively enhance the direct arylation reaction of
enaminone and arylboronic acid [14], we tried to employ the
copper salts for our model reaction. Encouragingly, when 0.5
equiv CuCl2 was used, the yield was increased obviously.
And other chloride salts like FeCl3, CeCl3 and NiCl2 were
also examined, FeCl3 was proved to be the best efficient ad-
ditive and the yield of target compound was increased upon
to 65% (entries 10-14). Among the solvents tested, DMF
was found to be more effective than other solvents such as
*Address correspondence to the author at the Department of Chemistry,
College of Science, Lishui University, Lishui, Zhejiang 323000, China;
E-mail: wxm7162@aliyun.com
1875-6255/13 $58.00+.00
© 2013 Bentham Science Publishers

Direct arylation of Azoles with Arylboronic Acids
Letters in Organic Chemistry, 2013, Vol. 10, No. 9 669
Table 1. Optimization of the Direct Arylation Conditionsa
Entry
Pd Catalyst [mol%]
Oxidant [equiv]
Additive [equiv]
Solvent
Yield(%)b
1
2
Pd(OAc)2(10)
PdCl2(10)
Pd(MeCN)2Cl2(10)
Pd/C(10)
Cu(OAc)2(1)
Cu(OAc)2(1)
Cu(OAc)2(1)
Cu(OAc)2(1)
Cu(OAc)2(1)
CuSO4(1)
/
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSOꢀ
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
30
32
27
12
0
/
3
/
4
/
5
/
/
6
PdCl2(10)
PdCl2(10)
PdCl2(10)
PdCl2(10)
PdCl2(10)
PdCl2(10)
PdCl2(10)
PdCl2(10)
PdCl2(10)
PdCl2(10)
PdCl2(10)
PdCl2(10)
PdCl2(10)
PdCl2(5)
/
22
30
12
<5
55
48
65
18
15
80
76
72
45
75
76
81
78
79
70
<5
55
7
CuCl2(1)
/
8
CuO(1)
/
9
K2S2O8(1)
/
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26c
Cu(OAc)2(1)
Cu(OAc)2(1)
Cu(OAc)2(1)
Cu(OAc)2(1)
Cu(OAc)2(1)
Cu(OAc)2(1)
Cu(OAc)2(1)
Cu(OAc)2(1)
Cu(OAc)2(1)
Cu(OAc)2(1)
Cu(OAc)2(1)
Cu(OAc)2(0.5)
Cu(OAc)2(1.5)
Cu(OAc)2(0.5)
Cu(OAc)2(0.5)
/
CuCl2(0.5)
CuCl(0.5)
FeCl3(0.5)
CeCl3(0.5)
NiCl2(0.5)
FeCl3(0.5)
FeCl3(0.5)
FeCl3(0.5)
FeCl3(0.5)
FeCl3(0.5)
FeCl3(0.5)
FeCl3(0.5)
FeCl3(0.5)
FeCl3(1)
FeCl3(0.3)
FeCl3(0.5)
FeCl3(0.5)
DMA
NMP
CH3CN
DMF
PdCl2(20)
PdCl2(10)
PdCl2(10)
PdCl2(10)
PdCl2(10)
PdCl2(10)
PdCl2(10)
DMF
DMF
DMF
DMF
DMF
DMF
Cu(OAc)2(0.5)
DMF
a Reaction conditions: benzothiazole (0.5 mmol); phenylboronic acid (1.0 mmol); solvent (2.0 mL); 120°C, 24h, in air. b Isolated yield. c Phenylboronic acid (0.5 mmol).
DMSO, NMP and CH3CN, to afford 2-phenylbenzothiazole
in 80% yield (entries 15-18). Further experiments showed
that decreasing the catalyst loading from 10 to 5 mol% re-
sulted in the decrease of the yield even under extended reac-
tion time conditions. In contrast, no significant improvement
of the yield was observed by increasing the catalyst loading
to 20 mol%. With respect to the amount of oxidant and addi-
tive used in the reaction, 0.5 equiv Cu(OAc)2 and 0.5 equiv
FeCl3 were found to be optimal (entries 19-24). The control
experiment also showed that Cu(OAc)2 was necessary for the
reaction to proceed (entry 25). In addition, decreasing the
amount of phenylboronic acid to 1 equiv resulted in a poor
yield due to the formation of biphenyl in a significant
amount even under the optimal conditions (entry 26). Thus,
the best result was obtained by using 0.5 equiv of Cu(OAc)2
as the oxidant, 0.5 equiv of FeCl3 as the additive in the pres-
ence of 10 mol% PdCl2 in DMF at 120°C for 24h.
The direct arylation between benzothiazole with various
arylboronic acids was investigated under the optimal condi-
tions and the results are shown in Table 2. For arylboronic
acids with different functional groups, including methyl,
methoxy, fluoro, and chloro groups on the para- or meta-
position of benzene rings, could react with benzothiazole
smoothly to generate the desired products in moderate to
good yields (Table 2, entries 1-7). Even arylboronic acid
with the steric hindrance substituent at ortho position was
tolerated in this reaction (entry 4). Remarkably, fluorobiaryl
products are popular in medicinal and materials chemistry,
and chloro-substituted benzothiazole would allow for further

670 Letters in Organic Chemistry, 2013, Vol. 10, No. 9
Wu and Shen
Table 2. Direct Arylation of Azole with Various Arylboronic Acidsa
N
Z
N
PdCl2, Cu(OAc)2
B(OH)2
+
Z=S, O, NCH3
R
FeCl3, DMF, 120°C
R
Z
Entry
Azole
Arylboronic Acids
Product
Yield(%)b
Ref.
B(OH)2
S
S
1
81
78
[8]
N
S
N
B(OH)2
B(OH)2
S
2
3
[8]
N
S
N
S
N
S
72
[5b]
N
B(OH)2
B(OH)2
S
4
5
53
68
[8]
[8]
N
S
N
S
Cl
N
S
N
Cl
Cl
Cl
B(OH)2
B(OH)2
S
6
70
[8]
N
S
N
S
F
7
8
65
85
[8]
N
O
N
F
B(OH)2
O
[5b,9]
N
O
N
O
B(OH)2
B(OH)2
B(OH)2
B(OH)2
9
78
75
72
65
[9]
N
N
N
N
10
11
12
[5b]
[5a]
[5a]
N
N
N
N
N
N
N
N
N
N
Cl
Cl
B(OH)2
B(OH)2
S
S
13
14
77
75
[5i]
N
S
N
S
[9,12]
N
N
a Reaction conditions: azole (0.5 mmol); arylboronic acid (1.0 mmol); PdCl2 (0.05mmol); Cu(OAc)2 (0.25 mmol); FeCl3 (0.25 mmol); DMF (2.0 mL); 120 °C, 24 h, in air. b Isolated
yield.

Direct arylation of Azoles with Arylboronic Acids
Letters in Organic Chemistry, 2013, Vol. 10, No. 9 671
2-(4-Methylphenyl)benzothiazole[8]
derivatization through cross-coupling reactions such as
Heck, Suzuki and Ullmann reactions, to feature the utility of
this protocol.
1
Yellow solid, mp 110-112°C (lit.: 110.3-112.7°C); H
NMR (300 MHz, CDCl3): ꢁ 2.42 (s, 3H), 7.28-7.39 (m, 3H),
7.45-7.50 (m, 1H), 7.87-8.07 (m, 4H); 13C NMR (CDCl3,
75MHz): ꢁ 21.5, 121.5, 123.0, 125.0, 126.2, 127.5, 129.7,
130.9, 134.9, 141.4, 154.1, 168.2; GC-MS (EI, m/z): 225
[M+].
We then investigated the reaction of other heterocycles
such as benzoxazole, 1-methylbenzimidazole and 4,5-
dimethylthiazole with arylboronic acids. Similar to the aryla-
tion of benzothiazole, various substituted arylboronic acids
successfully reacted with heterocycles to afford the corre-
sponding aryl-substitued azoles under the present reaction
conditions (entries 8-14). The yields for the arylation of 1-
methylbenzimidazole were a little lower than that for ben-
zothiazole and benzoxazole, which may arise from the dif-
ferent acidities of hydrogen at C-2 of heterocycles and is
consistent with the previous report [5a].
2-(3-Methylphenyl)benzothiazole[5b]
1
Yellow solid, mp 69-70°C (lit.: 71.5°C); H NMR (300
MHz, CDCl3): ꢁ 2.45 (s, 3H), 7.25-7.40 (m, 3 H), 7.46-7.52
(m, 1H), 7.85-7.94 (m, 3 H), 8.06-8.09 (m, 1H); 13C NMR
(CDCl3, 75MHz): ꢁ 21.3, 121.5, 123.2, 124.8, 125.1, 126.2,
128.0, 128.9, 131.8, 133.5, 135.0, 138.8, 154.1, 168.3; GC-
MS (EI, m/z): 225 [M+].
In summary, PdCl2 in conjunction with copper and iron
salts can effectively catalyze the arylation of the C-H bond
of heterocycles, such as benzothiazole, benzoxazole, 1-
methylbenzimidazole and 4,5-dimethylthiazole under ligand
and base-free conditions, to form the corresponding hetero-
cycle compounds in moderate to good yields. The extend
investigation of this kind reaction and mechanism is under-
way in our laboratory.
2-(2-Methylphenyl) benzothiazole[8]
1
Yellow solid, mp 55-57°C (lit.: 56.2-57.7°C); H NMR
(300 MHz, CDCl3): ꢁ 2.66 (s, 3H), 7.31ꢂ7.51 (m, 5H), 7.75
(d, J = 7.0 Hz, 1H), 7.93 (d, J = 7.5 Hz, 1H), 8.10 (d, J = 8.1
Hz, 1H); 13C NMR (CDCl3, 75MHz): ꢁ 21.3, 121.3, 123.3,
125.0, 126.0, 126.1, 129.9, 130.5, 131.5, 133.1, 135.5, 137.2,
153.7, 167.9; GC-MS (EI, m/z): 225 [M+].
EXPERIMENTAL
General
2-(4-Chlorophenyl)benzothiazole[8]
White solid, mp 109-110°C (lit.: 110.3-112.5°C); 1H
NMR (300 MHz, CDCl3): ꢁ 7.38-7.53(m, 4H), 7.89-8.08 (m,
4H); 13C NMR (CDCl3, 75MHz): ꢁ 121.6, 123.2, 125.4,
126.5, 128.7, 129.2, 132.0, 135.0, 137.0, 154.0, 166.6; GC-
MS (EI, m/z): 245 [M+].
All commercial reagents were used as received without
purification, and all solvents were of reagent grade. 1H NMR
and 13C NMR spectra were recorded at 300 MHz and 75
MHz with Bruker Avance 300 spectrometer using CDCl3 as
solvent and tetramethylsilane as internal standard. Melting
points were obtained from a XT4A melting point apparatus
and were uncorrected. Gas chromatography mass spectra
(GC/MS) were recorded on an Agilent Technologies 6890 N
instrument with an Agilent 5975 N mass detector (EI) and a
HP5-MS 30 mꢀ0.25 mm capillary apolar column.
2-(3-Chlorophenyl)benzothiazole[8]
1
White solid, mp 112-114°C (lit.: 112.3-114.2°C); H
NMR (300 MHz, CDCl3): ꢁ 7.41-7.51 (m, 4H), 7.90-8.12
(m, 4H); 13C NMR (CDCl3, 75MHz): ꢁ 121.7, 123.4, 125.5,
125.6, 126.5, 127.3, 130.2, 130.8, 135.0, 135.1, 135.2, 153.9,
166.2; GC-MS (EI, m/z): 245 [M+].
General Experimental Procedure
Azole (0.5 mmol), arylboronic acid (1.0 mmol), PdCl2
(0.05 mmol), Cu(OAc)2·H2O (0.25 mmol), FeCl3 (0.25
mmol) and DMF (2.0 mL) were taken in a 25 mL two-neck
flask. The mixture was heated at 120 °C in air for 24 h by
magnetic stirring. After cooling to room temperature, the
product was diluted with H2O (5 mL) and extracted with
EtOAc (4ꢀ15 mL). The extracts were combined and washed
by brine (3ꢀ10 mL), dried over MgSO4, filtered, and evapo-
rated, and purified by chromatography on silica gel to obtain
2-(4-Fluorophenyl)benzothiazole[8]
1
White solid, mp 109-111°C (lit.: 110.1-112.6°C); H
NMR (300 MHz, CDCl3): ꢁ 7.16-7.26 (m, 3H), 7.39-7.42
(m, 1H), 7.47-7.50 (m, 1H), 7.89-7.92 (m, 1H), 8.05-8.12
(m, 3H); 13C NMR (CDCl3, 75MHz): ꢁ 116.0, 116.3, 121.6,
123.2, 125.2, 126.4, 129.5, 129.6, 135.0, 154.0, 164.4, 166.7;
GC-MS (EI, m/z): 229 [M+].
the desired products
with
ethyl acetate/hexane
2-Phenylbenzoxazole[5b, 9]
(v/v=1:1ꢀ1:10). The products were characterized by their
spectral and analytical data and compared with those of the
known compounds.
White solid, mp100-102°C (lit.: 102.8°C); 1H NMR (300
MHz, CDCl3): ꢁ 7.26-7.27 (m, 1H), 7.35-7.38 (m, 2H), 7.53-
7.61 (m, 3H), 7.79-7.80 (m, 1H), 8.27-8.29 (m, 2H); 13C
NMR (CDCl3, 75MHz): ꢁ 110.6, 120.0, 124.5, 125.1, 127.2,
127.6, 128.9, 131.5, 142.1, 150.7, 163.1; GC-MS (EI, m/z):
229 [M+].
Characterization Data of All the Products
2-Phenylbenzothiazole[8]
1
White solid, mp 97-99°C (lit.: 98.1-100.7°C); H NMR
2-(3-Methylphenyl) benzoxazole[9]
(300 MHz, CDCl3): ꢁ 7.36-7.42 (m, 1H), 7.48-7.50 (m, 4H),
7.90-7.92 (m, 1H), 8.07-8.11 (m, 3H); 13C NMR (CDCl3,
75MHz): ꢁ 121.6, 123.2, 125.2, 126.3, 127.5, 129.0, 130.9,
133.6, 134.9, 154.0, 168.0; GC-MS (EI, m/z): 211 [M+].
1H NMR (300 MHz, CDCl3): ꢁ 2.44 (s, 3H), 7.26 (s, 1H),
7.34-7.40 (m, 3H), 7.57-7.58 (m, 1H), 7.76-7.80 (m, 1H),
8.05-8.11 (m, 2H); 13C NMR (CDCl3, 75MHz): ꢁ 21.3,

672 Letters in Organic Chemistry, 2013, Vol. 10, No. 9
Wu and Shen
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142.1, 150.7, 163.2; GC-MS (EI, m/z): 229 [M+].
2-Phenyl-1-methyl-1H-benzo[d]imidazole[5b]
1
White solid, mp 92-94°C (lit.: 94.7°C); H NMR (300
MHz, CDCl3): ꢀ 3.88 (s, 3H), 7.30-7.37 (m, 2H), 7.38-7.42
(m, 1H), 7.48-7.57 (m, 3H), 7.75-7.80 (m, 3H), 7.80-7.88
(m, 1H). 13C NMR (CDCl3, 75MHz): ꢀ 31.7, 109.6, 119.9,
122.4, 122.7, 128.7, 129.5, 129.7, 130.2, 136.6, 143.0, 153.8.
2-(p-Tolyl)-1-methyl-1H-benzo[d]imidazole[5a]
1
White solid, mp 125-127°C (lit.: 127-128°C); H NMR
(3,4-Dimethoxyphenyl)-5-fluorobenzothiazole
(GW
610,
(300 MHz, CDCl3): ꢀ 2.44 (s, 3H), 3.87 (s, 3H), 7.30-7.40
(m, 5H), 7.65-7.68 (m, 2H), 7.82-7.85 (m, 1H); 13C NMR
(CDCl3, 75MHz): ꢀ 21.5, 31.7, 109.6, 119.6, 122.5, 122.6,
127.3, 129.3, 129.4, 136.6, 140.0, 142.5, 153.9; GC-MS (EI,
m/z): 223 [M+].
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2-(4-Chlorophenyl)-1-methyl-1H-benzo[d]imidazole[5a]
[2]
1
White solid, mp 111-113°C (lit.: 112-113°C); H NMR
(300 MHz, CDCl3): ꢀ 3.90 (s, 3H), 7.33-7.49 (m, 5H), 7.65-
7.67 (m, 1H), 7.80-7.85 (m, 2H); 13C NMR (CDCl3,
75MHz): ꢀ 31.6, 109.7, 120.0, 122.7, 123.2, 127.5, 129.5,
129.8, 129.9, 134.8, 136.5, 142.8, 152.5; GC-MS (EI, m/z):
243 [M+].
4,5-Dimethyl-2-phenylthiazole[5i]
1
Colorless oil; H NMR (300 MHz, CDCl3): ꢀ 2.40 (s,
6H), 7.26-7.42 (m, 3H), 7.87-7.89 (m, 2H); 13C NMR
(CDCl3, 75MHz): ꢀ 11. 5, 14.8, 126.1, 126.5, 128.7, 129.3,
133.9, 149.2, 163.3; GC-MS (EI, m/z): 189.
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1
Colorless solid, mp 56-58°C (lit.:56-57°C); H NMR
(300 MHz, CDCl3): ꢀ 2.37 (s, 9H), 7.20 (d, J = 7.8 Hz, 2H),
7.76 (d, J = 7.8 Hz, 2H); 13C NMR (CDCl3, 75MHz): ꢀ 11.4,
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CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flict of interest.
ACKNOWLEDGEMENTS
This work was supported by the Natural Science Founda-
tion of Zhejiang Province (NO. LY13B020005).
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