Ligand-free CuO nanospindle catalyzed arylation of heterocycle C-H bonds

Article abstract of DOI:10.1021/jo200452x

CuO nanospindles have been developed to efficiently catalyze the direct arylation of heterocycle C-H bonds with moderate to excellent yields. This reaction can be applied to heterocycles such as benzoxazole, benzothiazole, and 1-methylbenzimidazole in the presence of a more environmentally friendly inorganic base like K₂CO₃ under ligand-free catalytic conditions. In addition, the catalyst can be recycled and reused without any significant decrease in catalytic activity.

Full text of DOI:10.1021/jo200452x

NOTE
pubs.acs.org/joc
Ligand-Free CuO Nanospindle Catalyzed Arylation of Heterocycle
CꢀH Bonds
Wu Zhang,* Qinglong Zeng, Xinming Zhang, Yujie Tian, Yun Yue, Yujun Guo, and Zhenghua Wang*
Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Laboratory of Molecule-Based Materials, College of
Chemistry and Materials Science, Anhui Normal University, Wuhu 241000, People’s Republic of China
S Supporting Information
b
ABSTRACT: CuO nanospindles have been developed to
efficiently catalyze the direct arylation of heterocycle CꢀH
bonds with moderate to excellent yields. This reaction can be
applied to heterocycles such as benzoxazole, benzothiazole, and
1-methylbenzimidazole in the presence of a more environmen-
tally friendly inorganic base like K2CO3 under ligand-free
catalytic conditions. In addition, the catalyst can be recycled
and reused without any significant decrease in catalytic activity.
eterocycles are one of the most important organic structural
motifs in a myriad of pharmaceutically active compounds
environmentally friendly mild base, the development of an
efficient ligand-free reaction system with recyclable copper
catalysts in the presence of mild inorganic base is highly desirable.
Nanoparticles have emerged as robust and high surface area
heterogeneous catalysts,8 which serve as a sustainable alternatives
to conventional materials, especially CuO nanoparticles due to
their stability and wild availability. Recently, CuO nanoparticle-
catalyzed CꢀN, CꢀO, and CꢀS cross-coupling reactions have
been achieved.9 However, to the best of our knowledge, the
application of these CuO nanoparticles in the catalyzed aryla-
tions of heterocycle CꢀH bonds have not been reported. Since
the size, shape, and morphology of catalyst particles have signif-
icant effects on the catalytical properties of the catalyst,10 herein
we report a general efficient method for the CuO nanospindles-
catalyzed arylation of heterocycles with aryl iodides.
The optimization of the reaction conditions for our CuO
nanospindle-catalyzed arylation reaction was performed using
benzoxazole and iodobenzene as substrates as summarized in
Table 1. The absence of either CuO nanospindles or bases fails to
generate the desired products, and all the starting materials were
recovered from the reaction system (Table 1, entries 13 and 14).
Decreasing the catalyst loading from 10 to 5 mol % resulted in the
decrease of the yield even under extended reaction time condi-
tions (Table 1, entry 15). In contrast, no significant improvement
of the yield was observed by increasing the catalyst loading to
20 mol % (Table 1, entries 16 and 17). Reaction temperature also
has some effect on this reaction (for example, 41% yield at 150 °C
and 13% yield at 140 °C). In addition, the size of the CuO was
observed to affect the reaction, and the substitution of CuO
nanospindles with the commercial CuOpowder(about 200 mesh)
only gave the desired product in 39% yield (Table 1, entry 20).
Thus, by varying the solvents and bases, the optimal reaction
H
and organic materials.1 Therefore, the efficient synthesis of
heterocycles and their derivatives has been a topic of great
interest from the perspective of medicinal chemistry and organic
synthesis.2 Among these methods, the simplest approach is the
arylation of heterocycle CꢀH bonds. In the past decades,
transition metals have been widely used as the efficient catalysts
for various cross-coupling reactions,3 including the rhodium-4
and palladium-catalyzed5 direct arylation of various heteroer-
enes. However, these reactions have limited applications in the
industry due to the relatively high cost of the catalyst. Therefore,
the development of an inexpensive and efficient catalysts for this
reaction has received wide research interest. For example, nickel-
catalyzed direct arylation and alkenylation of heterocycle CꢀH
bonds have been successfully developed.6
Copper catalysts, as a complementary approach to the con-
ventionally expensive Rh and Pd catalysts, have been receiving
much attention in cross-coupling reactions because of their
excellent catalytic properties. Recently, Daugulis and co-workers
have reported the CuI-catalyzed arylation of heterocycle CꢀH
Bonds using LiOtBu as the base.7a Later on, they extended this
CuI-catalyzed reaction to the arylation of arene CꢀH bonds by
introducing phenanthroline into the catalytic system.7b Mean-
while, Miura and co-workers have described the CuI/PPh3-
catalyzed direct arylation of benzoazoles with aryl iodides,7c
and the CuI-catalyzed direct alkenylation of oxazoles with
bromoalkenes using trans-N,N0-dimethylcyclohexane-1,2-dia-
mine as ligand has also been reported by Piguel et al.7d In
2009, You and co-workers also reported the CuI-catalyzed direct
arylation of heterocycles with aryl bromides using 1,10-phenan-
throline as a ligand.7e However, these CuI-catalyzed reaction
systems require the presence of organic ligands which make it
difficult for the separation and purification after the reactions.
Considering the preference of modern green chemistry for more
Received: March 5, 2011
Published: April 20, 2011
r
2011 American Chemical Society
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|

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NOTE
Table 1. Optimization of the Arylation Conditionsa
Table 2. Arylation Scope with Respect to Aryl Iodides and
Heterocyclesa
entry
CuO (mol %)
base
solvent
T/°C
yield (%)
1
2
10
10
10
10
10
10
10
10
10
10
10
10
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
NaOAc
NEt3
DMF
reflux
reflux
reflux
160
56
DMSO
dioxane
NMP
44
3
trace
4
5
toluene
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
150
6
93
7
81
8
trace
9
10
11
12
13
14
15b
16
17
18
19
20c
K3PO4
KOtBu
K2CO3
53
11
10
5
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
71
95
96
41
13
39
15
20
10
10
10
140
reflux
a Reaction conditions: benzoxazole (1 equiv), iodobenzene (2 equiv),
base (2 equiv), solvent (2 mL), under reflux in argon for 3 h. b Reaction
time of 48 h. c CuO (200 mesh) was used instead of CuO nanospindles.
conditions were set to be 10 mol % of CuO nanospindles in the
presence of 2 equiv of K2CO3 in refluxing diglyme for 3 h. Under
these optimized reaction conditions, the desired arylation pro-
duct was obtained in 93% yield.
These optimized reaction conditions were then applied to the
arylation of a series of aryl halides as summarized in Table 2, and
moderate to excellent yields were achieved for substituted aryl
iodides with both electron-donating and electron-withdrawing
substituents (Table 2, entries 1ꢀ7). In general, the presence of
electron-withdrawing groups on aryl iodides leads to higher
arylation yields than those with electron-donating groups. This
may be due to the fact that the rate-determining step is the
oxidative addition process in this reaction, thus rendering a faster
reaction rate for the substrate with electron-withdrawing group.
Interestingly, even aryl iodide with the steric hindrance substi-
tuent at ortho position was tolerated in this reaction (Table 2,
entry 4). It is noteworthy that this reaction system could tolerate
various functional groups such as COOEt and CN. Unfortu-
nately, the substitution of aryl iodides with aryl bromides fails to
generate the desired products.
We then investigated the reaction of other heterocycles such
as benzothiazole and 1-methylbenzimidazole with aryl iodides,
and the results are summarized in Table 2 (entries 8ꢀ21).
Increasing the reaction time leads to an increase of the product
yield, with the best results obtained at 8 and 16 h, respectively.
The yields for the arylation of 1-methylbenzimidazole with aryl
iodides were lower than that for benzoxazole, which may arise
from the different acidities of hydrogen at C-2 of heterocycles.11
a Reaction conditions: heterocycle (1 equiv), aryl halide (2 equiv),
K2CO3 (2 equiv), diglyme (2 mL), under reflux in argon. The reaction
times are 3, 8, and 16 h for benzoxazole, benzothiazole, and 1-methyl-
benzimidazole, respectively.
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NOTE
Table 3. Successive Tests by Using Recycled CuO
Nanospindlesa
Scheme 1. Proposed Catalytic Cycle
test
yield (%)
1
2
3
93
91
88
a Reaction conditions: benzoxazole (1 equiv), iodobenzene (2 equiv),
10 mol % of CuO nanospindles, K2CO3 (2 equiv), diglyme (2 mL),
under reflux in argon for 3 h.
However, the yields of benzothiazole with aryl iodides were the
lowest in the reaction system, which could be attributed to the
fact that there is a equilibrium between the ring-opened isomer
with azole anion upon deprotonation.12 The resulting phenthiol
species could have a relative higher reactivity with aryl iodides to
generate the byproduct N,N-diphenyl-2-phenylthioaniline7c be-
cause of the stronger nucleophilicity of phenthiol species com-
pared to phenol species. The detailed ring-opening process of
benzothiazole in this reaction is still under the investigation.
The recyclability of the CuO nanospindles was also tested as
shown in Table 3. No significant decrease in the catalytic activity
for the arylation of benzoxazole with iodobenzene was observed
for the recovered CuO nanospindles. XRD of the catalysts after
the reaction demonstrated that the catalysts did not change
during the reaction process (Figure S1, Supporting Information),
and SEM of the catalysts after the reaction implied slight
assemblage of the CuO nanospindles (Figure S2, Supporting
Information). To further identify the recycled catalyst, energy-
dispersive spectrometry (EDS) analysis was also performed,
which reveals that the sample is essentially pure copper oxide without
the presence of iodine (Figure S3, Supporting Information).
It is very necessary to further investigate whether this observed
active catalysis is derived either from CuO nanospindles or the
leached copper species.13 The arylation of benzoxazole was then
performed under the optimized conditions, and the catalyst was
removed from the mixture by centrifugation after 1 h (at this
time, approximately 50% yield was obtained). The “catalyst-free”
mixture was continued to react under the same reaction condi-
tions, which showed no further reaction progress even after 3 h.
Leaching of the copper from the CuO nanospindles during the
reaction was examined by AAS analysis, and a slight leaching (<1
ppm) was observed. Therefore, the reaction was believed to
occur on the surface of the CuO nanospindles via a hetero-
geneous process.
Scheme 2. H/D Exchange Experiment
removed in the presence of K2CO3 without the copper catalyst,
which is consistent with the previous report.12b
In summary, CuO nanospindles can effectively catalyze the
arylation of the CꢀH bond of heterocycles, such as benzoxazole,
benzothiazole and 1-methylbenzimidazole, in a ligand-free cou-
pling reaction system, to form the corresponding heterocycle
compounds in moderate to excellent yields. A more environ-
mentally friendly mild base can be used instead of a strong base
such as LiOtBu. It is also noteworthy to point out that the catalyst
can be recycled and reused without any significant decrease in the
catalytic activity.
’ EXPERIMENTAL SECTION
General Methods. The prepared CuO products were character-
ized by X-ray powder diffraction with graphite-monochromatized Cu
KR radiation (λ = 0.154060 nm), employing a scanning rate of 0.02° sꢀ1
in the 2θ range from 10° to 80°. The field-emission scanning electron
microscopy (FE-SEM) images were obtained with an accelerating
1
voltage of 5 kV. NMR spectra were obtained at 300 MHz for H and
at 75 MHz for 13C NMR, and chemical shifts for 1H and 13C were both
referenced to CDCl3. High-resolution mass spectral (HRMS) data were
obtained with an ionization mode of ESI.
All starting materials and reagents were commercially available and
used without further purification. All products were purified and
A possible mechanism for this CuO nanospindles-catalyzed
direct arylation of heterocycle was proposed. The reaction may
undergo through an oxidative addition subsequent anion sub-
stitution, followed by a reductive elimination process on the
surface of the CuO nanospindles (Scheme 1), similar to that for
many of the heterogeneous processes reported in the literature.9
To further check the alternative mechanism through σ-adduct
formation at the metal center followed by elimination,14 the H/D
exchange of the benzothiazole has also been carried out with
K2CO3 in the absence of CuO catalysts (Scheme 2). The result
indicated that the hydrogen at C-2 of the heterocycle can be
1
characterized by H NMR and 13C NMR. The spectroscopic data of
the known compounds are in accordance with those reported in the
literatures.15
Recycling Procedure of the Catalysts. The separated precipi-
tates in the above procedure were washed sufficiently with deionized
water and ethanol three times each and then dried under vacuum at
50 °C for 8 h, and then the CuO nanospindles were recovered.
Typical Procedure for CuO-Catalyzed Arylation of Ben-
zoxazole and 4-Iodoanisole. The CuO nanospindles were pre-
pared by thermal dehydration of the freshly prepared Cu(OH)2 in
solution.16Benzoxazole (0.5 mmol), 4-iodoanisole (1 mmol), CuO
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NOTE
nanospindles (10 mol %), and K2CO3 (1 mmol) were stirred in diglyme
(2 mL) under reflux in argon for 3ꢀ16 h. The resulting mixture was
cooled to room temperature and then centrifuged. The organic phase
was separated; the precipitate was washed thoroughly with EtOAc and
then centrifuged. The organic phases were combined, washed with brine
(3 ꢁ 10 mL), dried over anhydrous magnesium sulfate, and concen-
trated under reduced pressure. The residue was purified by column
chromatography on silica gel (EtOAc/petroleum = 1/3) to afford the
product 2-(2-methoxyphenyl)benzo[d]oxazole (Table 2, entry 4):
136.7, 134.3, 131.5, 129.9, 129.4, 123.3, 122.8, 120.1, 109.8, 61.3, 31.8,
14.3; HRMS (ESI) calcd for C17H17N2O2 ([M þ H]þ) 281.1290, found
281.1284.
4-(1-Methyl-1H-benzo[d]imidazol-2-yl)benzonitrile (Table 2,
1
entry 21): white solid; yield 88%; mp 208ꢀ209 °C; H NMR (300
MHz, CDCl3) δ 7.94ꢀ7.91 (d, J = 7.8 Hz, 2H), 7.85ꢀ7.83 (m, 3H),
7.42ꢀ7.37 (m, 3H), 3.91 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 151.4,
142.9, 136.7, 134.6, 132.5, 130.0, 123.7, 123.1, 120.2, 118.3, 113.4, 109.9,
31.9; HRMS (ESI) calcd for C15H12N3 ([M þ H]þ) 234.1031, found
234.1019.
1
white solid; yield 80%; mp 46ꢀ47 °C; H NMR (300 MHz, CDCl3)
δ 8.15ꢀ8.12 (d, J = 7.6 Hz, 1H), 7.84ꢀ7.82 (m, 1H), 7.59ꢀ7.48 (m,
2H), 7.36ꢀ7.35 (m, 2H), 7.13ꢀ7.08 (m, 2H), 4.02 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 161.6, 158.5, 150.4, 142.1, 132.8, 131.3, 124.9,
124.3, 120.7, 120.2, 116.2, 112.1, 110.5, 56.2. HRMS (ESI) calcd for
C14H12NO2 ([M þ H]þ) 226.0868, found 226.0858.
’ ASSOCIATED CONTENT
S
Supporting Information. Catalyst characterization (XRD,
b
SEM, and EDS) and NMR (1H and 13C) spectra of all products.
This material is available free of charge via the Internet at http://
pubs.acs.org.
Ethyl 4-(benzo[d]oxazol-2-yl)benzoate (Table 2, entry 6):
white solid; yield 82%; mp 160ꢀ161 °C; 1H NMR (300 MHz, CDCl3) δ
8.33ꢀ8.31 (d, J = 7.7 Hz, 2H), 8.20ꢀ8.17 (d, J = 7.5 Hz, 2H), 7.81ꢀ7.80
(m, 1H), 7.60ꢀ7.59 (m, 1H), 7.40ꢀ7.38 (m, 2H), 4.45ꢀ4.38 (q, J = 6.9
Hz, 2H), 1.44ꢀ1.40 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
165.9, 162.0, 150.9, 142.0, 132.9, 130.9, 130.1, 127.5, 125.7, 124.9, 120.4,
110.8, 61.4, 14.3; HRMS (ESI) calcd for C16H14NO3 ([M þ H]þ)
268.0974, found 268.0958.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: zhangwu@mail.ahnu.edu.cn; zhwang@mail.ahnu.edu.cn.
Ethyl 4-(benzo[d]thiazol-2-yl)benzoate (Table 2, entry 13):
white solid; yield 60%; mp 135ꢀ136 °C; 1H NMR (300 MHz, CDCl3) δ
8.15ꢀ8.08 (m, 5H), 7.92ꢀ7.90 (d, J = 7.8 Hz, 1H), 7.53ꢀ7.48 (m, 1H),
7.43ꢀ7.38 (m, 1H), 4.44ꢀ4.37 (q, J = 7.0 Hz, 2H), 1.44ꢀ1.39 (t, J = 6.8
Hz, 3H); 13C NMR (75MHz, CDCl3) δ 166.7, 165.9, 154.1, 137.4, 135.3,
132.4, 130.2, 127.4, 126.6, 125.7, 123.6, 121.7, 61.3, 14.3; HRMS (ESI)
calcd for C16H14NO2S ([M þ H]þ) 284.0745, found 284.0732.
2-(4-Chlorophenyl)-1-methyl-1H-benzo[d]imidazole(Table2,
’ ACKNOWLEDGMENT
We are grateful to the National Natural Science Foundation of
China (20972002) and the Education Department of Anhui
province (TD200707) for financial support.
1
’ REFERENCES
entry 16): white solid; yield 83%; mp 112ꢀ113 °C; H NMR (300
MHz, CDCl3) δ 7.81ꢀ7.80 (m, 1H), 7.69ꢀ7.66 (d, J = 7.5 Hz, 2H),
7.49ꢀ7.46 (d, J = 7.5 Hz, 2H), 7.33ꢀ7.31 (m, 3H), 3.80 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 152.5, 142.9, 136.6, 136.0, 130.7, 129.0,
128.7, 123.0, 122.6, 119.9, 109.7, 31.7; HRMS (ESI) calcd for
C14H12N2Cl ([M þ H]þ) 243.0689, found 243.0678.
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2-(4-Methoxyphenyl)-1-methyl-1H-benzo[d]imidazole
1
(Table 2, entry 17): white solid; yield 79%; mp 118ꢀ119 °C; H
NMR (300 MHz, CDCl3) δ 7.81ꢀ7.80 (m, 1H), 7.70ꢀ7.67 (d, J = 7.6
Hz, 2H), 7.32ꢀ7.28 (m, 3H), 7.03ꢀ7.00 (d, J = 7.6 Hz, 2H), 3.85
(s, 3H), 3.80 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 160.8, 153.8, 142.9,
136.6, 130.8, 122.5, 122.3, 119.5, 114.1, 109.5, 55.4, 31.7; HRMS (ESI)
calcd for C15H15N2O ([M þ H]þ) 239.1184, found 239.1172.
2-(2-Methoxyphenyl)-1-methyl-1H-benzo[d]imidazole
1
(Table 2, entry 18): yellow oil; yield 75%; H NMR (300 MHz,
CDCl3) δ 7.82ꢀ7.81 (m, 1H), 7.58ꢀ7.56 (d, J = 7.1 Hz, 1H),
7.49ꢀ7.44 (m, 1H), 7.35ꢀ7.28 (m, 3H), 7.11ꢀ7.06 (m, 1H),
7.00ꢀ6.97 (d, J = 8.1 Hz, 1H), 3.76 (s, 3H), 3.61 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 157.5, 152.2, 143.1, 136.1, 132.3, 131.6, 122.5,
122.0, 121.0, 119.8, 119.6, 111.1, 109.5, 55.6, 30.9; HRMS (ESI) calcd
for C15H15N2O ([M þ H]þ) 239.1184, found 239.1177.
1-Methyl-2-(p-tolyl)-1H-benzo[d]imidazole (Table 2, entry
1
19): white solid; yield 70%; mp 127ꢀ128 °C; H NMR (300 MHz,
CDCl3) δ 7.83ꢀ7.81 (m, 1H), 7.66ꢀ7.63 (d, J = 7.2 Hz, 2H),
7.33ꢀ7.30 (m, 5H), 3.82 (s, 3H), 2.43 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 153.9, 143.0, 139.9, 136.6, 129.4, 129.3, 127.3, 122.6, 122.4,
119.7, 109.6, 31.7, 21.5; HRMS (ESI) calcd for C15H15N2 ([M þ H]þ)
223.1235, found 223.1224.
Ethyl
4-(1-methyl-1H-benzo[d]imidazol-2-yl)benzoate
1
(Table 2, entry 20): white solid; yield 80%; mp 129ꢀ130 °C; H
NMR (300 MHz, CDCl3) δ 8.21ꢀ8.19 (d, J = 8.0 Hz, 2H), 7.88ꢀ7.85
(m, 3H), 7.40ꢀ7.35 (m, 3H), 4.46ꢀ4.39 (m, 2H), 3.89 (s, 3H),
1.45ꢀ1.40 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 166.0, 152.6,
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NOTE
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