Ligand-free direct C-arylation of heterocycles with aryl halides over a metal-organic framework Cu2(BPDC)2(BPY) as an efficient and robust heterogeneous catalyst

Article abstract of DOI:10.1016/j.molcata.2014.03.017

A crystalline porous metal-organic framework Cu₂(BPDC) ₂(BPY) was synthesized and characterized by X-ray powder diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), thermogravimetric analysis (TGA), Fourier transform infrared (FT-IR), atomic absorption spectrophotometry (AAS), hydrogen temperature-programmed reduction (H₂-TPR), and nitrogen physisorption measurements. The Cu₂(BPDC)₂(BPY) exhibited high catalytic activity in direct CH arylation reactions between heterocyles and aryl halides. The Cu ₂(BPDC)₂(BPY)-catalyzed CH arylation reaction could proceed to higher conversion than that of the reaction using Cu ₃(BTC)₂, Cu(BDC), Cu(BPDC), and Cu₂(BDC) ₂(BPY) as catalyst. Furthermore, under our conditions, the Cu ₂(BPDC)₂(BPY) also exhibited significantly higher activity than that of common copper salts, including Cu(NO₃)₂, CuCl, CuCl₂, and CuI. Excellent reusability of the Cu-MOF in the direct heterocycle CH arylation reaction was achieved.

Full text of DOI:10.1016/j.molcata.2014.03.017

Accepted Manuscript
Title: Ligand-free direct C-arylation of heterocycles with aryl
halides over a metal-organic framework Cu (BPDC) (BPY)
2
2
as an efficient and robust heterogeneous catalyst
Author: Hanh T.N. Le Tung T. Nguyen Phuong H.L. Vu
Thanh Truong Nam T.S. Phan
PII:
S1381-1169(14)00113-7
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.molcata.2014.03.017
MOLCAA 9051
To appear in:
Journal of Molecular Catalysis A: Chemical
Received date:
Revised date:
Accepted date:
12-9-2013
5-3-2014
6-3-2014
Please cite this article as: H.T.N. Le, T.T. Nguyen, P.H.L. Vu, T. Truong,
N.T.S. Phan, Ligand-free direct C-arylation of heterocycles with aryl halides
over a metal-organic framework Cu (BPDC) (BPY) as an efficient and robust
2
2
heterogeneous catalyst, Journal of Molecular Catalysis A: Chemical (2014),
http://dx.doi.org/10.1016/j.molcata.2014.03.017
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Ligand-free direct C-arylation of heterocycles with aryl halides over a metal-organic
framework Cu (BPDC) (BPY) as an efficient and robust heterogeneous catalyst
2
2
*
Hanh T. N. Le, Tung T. Nguyen, Phuong H. L. Vu, Thanh Truong, Nam T. S. Phan
Department of Chemical Engineering, HCMC University of Technology, VNU-HCM,
2
68 Ly Thuong Kiet, District 10, Ho Chi Minh City, Viet Nam
*
Email: HU ptsnam@hcmut.edu.vn
U
Ph: (+84 8) 38647256 ext. 5681
Fx: (+84 8) 38637504
Abstract
A crystalline porous metal-organic framework Cu (BPDC) (BPY) was synthesized and
2
2
characterized by X-ray powder diffraction (XRD), scanning electron microscopy (SEM),
transmission electron microscopy (TEM), thermogravimetric analysis (TGA), Fourier transform
infrared (FT-IR), atomic absorption spectrophotometry (AAS), hydrogen temperature-
programmed reduction (H -TPR), and nitrogen physisorption measurements. The
2
Cu (BPDC) (BPY) exhibited high catalytic activity in direct C-H arylation reactions between
2
2
heterocyles and aryl halides. The Cu (BPDC) (BPY)-catalyzed C-H arylation reaction could
2
2
proceed to higher conversion than that of the reaction using Cu (BTC) , Cu(BDC), Cu(BPDC),
3
2
and Cu (BDC) (BPY) as catalyst. Furthermore, under our conditions, the Cu (BPDC) (BPY)
2
2
2
2
also exhibited significantly higher activity than that of common copper salts, including
Cu(NO ) , CuCl, CuCl , and CuI. Excellent reusability of the Cu-MOF in the direct heterocycle
3
2
2
C-H arylation reaction was achieved.
Keywords: Metal-organic framework; benzoxazole; C-H activation; heterogeneous catalyst;
Cu (BPDC) (BPY).
2
2
1
Page 1 of 35

1
. Introduction
Aryl-substituted benzoxazoles have recently attracted significant attention as versatile
intermediates for the synthesis of a variety of biologically important natural products and
pharmaceuticals as well as functional polymers [1-3]. These structures are conventionally
achieved by the palladium-catalyzed cross-coupling of either heteroaryl halides with arylmetals
or aryl halides with heteroarylmetals, thus suffering disadvantages in terms of atom-economical
and environmental aspects [4]. The C-arylation of benzoxazoles with aryl halides via the direct
activation of C-H bonds would offer shorter and more efficient synthetic schemes as the
stoichiometric pre-metalation of the heterocycles or the aryl halides could be avoided [5-13].
Although this transformation could proceed readily in the presence of palladium- [14], or
rhodium [15] phosphine catalysts, the high cost of the metals still remains as a major concern.
Daugulis and Do previously demonstrated a significant breakthrough on the copper-catalyzed
direct heterocycle C-H arylation reaction between benzoxazole and iodobenzene using CuI as the
catalyst [16]. Miura [2], You [17] and co-workers then expanded the protocol, though CuI was
still employed as the catalyst, and triphenyphosphine [2] or 1,10-phenanthroline [17] as the
ligand was required. Under the view of green chemistry, the reaction using a heterogeneous
catalyst should be developed, facilitating the ease of handling, simple workup, recyclability and
reusability [18]. Recently, Zhang and co-workers reported the first example of a heterogeneous
C-H arylation reaction between benzoxazole and iodobenzene using CuO nanoparticles as the
catalyst [19]. The exploration of heterogeneous catalysts for the direct heterocycle C-H arylation
reactions should be undoubtedly an area that will attract further research in the near future.
2
Page 2 of 35

Metal-organic frameworks (MOFs) have been considered as promising materials in several fields
including gas separation and storage, sensors and luminescence, drug storage and delivery,
templated low-dimensional material preparation, and catalysis [20-25]. Although the application
of MOFs in catalysis has just been investigated for the past few years, several MOFs have
exhibited their potential applications for a variety of organic transformations [26, 27], ranging
from carbon-carbon [28-33] to carbon-heteroatom [34-37] forming reactions. Among several
popular MOFs, two Cu-MOFs Cu (BTC) [38-41] and Cu(BDC) [42, 43] have been employed as
3
2
catalysts in various organic transformations due to their unsaturated open copper metal sites. We
recently demonstrated that the Cu-MOF Cu (BPDC) (BPY) could offer high activity for the
2
2
coupling reaction of 2-substituted phenols with ethers [44] and with DMF [45], respectively. In
this work, we wish to report the copper-catalyzed direct heterocycle C-H arylation reaction
between benzoxazole and aryl halides using the Cu (BPDC) (BPY) as an efficient heterogeneous
2
2
catalyst. The catalyst could be easily isolated from the reaction mixture and could be reused
without significant degradation in activity. Moreover, the Cu (BPDC) (BPY) exhibited
2
2
significantly higher catalytic activity than that of other Cu-MOFs such as Cu (BTC) , Cu(BDC),
3
2
Cu(BPDC), and Cu (BDC) (BPY), and that of common copper salts such as CuCl , CuCl, CuI,
2
2
2
Cu(NO ) , and Cu(OAc) .
3
2
2
2
. Experimental
2
.1. Materials and instrumentation
All reagents and starting materials were obtained commercially from Sigma-Aldrich and Merck,
and were used as received without any further purification unless otherwise noted. Nitrogen
3
Page 3 of 35

physisorption measurements were conducted using a Micromeritics 2020 volumetric adsorption
o
analyzer system. Samples were pretreated by heating under vacuum at 150 C for 3 h. A Netzsch
Thermoanalyzer STA 409 was used for thermogravimetric analysis (TGA) with a heating rate of
o
1
0 C/min under a nitrogen atmosphere. X-ray powder diffraction (XRD) patterns were recorded
using a Cu Kα radiation source on a D8 Advance Bruker powder diffractometer. Scanning
electron microscopy studies were conducted on a S4800 Scanning Electron Microscope (SEM).
Transmission electron microscopy studies were performed using a JEOL JEM 1400
Transmission Electron Microscope (TEM) at 100 kV. The Cu (BPDC) (BPY) sample was
2
2
dispersed on holey carbon grids for TEM observation. Elemental analysis with atomic absorption
spectrophotometry (AAS) was performed on an AA-6800 Shimadzu. Fourier transform infrared
(FT-IR) spectra were obtained on a Nicolet 6700 instrument, with samples being dispersed on
potassium bromide pallets. The chemisorption experiments were studied in a Micromeritics 2020
analyzer. For hydrogen temperature programmed reduction (H -TPR), the sample was outgassed
2
o
at 100 C for 30 min with helium, then cooled down to room temperature, and exposed to 50
o
o
mL/min of 10% H /Ar as the temperature ramped at 2.5 C/min to 600 C. The amount of
2
hydrogen consumption was determined from TCD signal intensities, which were calibrated using
an Ag O reference sample.
2
Gas chromatographic (GC) analyses were performed using a Shimadzu GC 2010-Plus equipped
with a flame ionization detector (FID) and an SPB-5 column (length = 30 m, inner diameter =
0
.25 mm, and film thickness = 0.25 μm). The temperature program for GC analysis held samples
o
o
o
o
at 100 C for 1 min; heated them from 100 to 180 C at 40 C/min; held them at 180 C for 1
o
o
o
min; heated them from 180 to 280 C at 50 C/min and held them at 280 C for 2 min. Inlet and
4
Page 4 of 35

o
detector temperatures were set constant at 280 C. n-Hexadecane was used as an internal
standard to calculate reaction conversions. GC-MS analyses were performed using a Hewlett
Packard GC-MS 5972 with a RTX-5MS column (length = 30 m, inner diameter = 0.25 mm, and
film thickness = 0.5 μm). The temperature program for GC-MS analysis heated samples from 60
o
o
o
to 280 C at 10 C/min and held them at 280 C for 2 min. Inlet temperature was set constant at
o
2
80 C. MS spectra were compared with the spectra gathered in the NIST library.
2
.2. Synthesis of the metal-organic framework Cu (BPDC) (BPY)
2
2
In a typical preparation, a solid mixture of H BPDC (H BPDC = 4,4’-biphenyldicarboxylic acid;
2
2
0
.1039 g, 0.4 mmol), BPY (BPY = 4,4’-bipyridine; 0.033 g, 0.2 mmol), and Cu(NO ) .3H O
3 2 2
(0.105 g, 0.4 mmol) was dissolved in a mixture of DMF (DMF = N,N’-dimethylformamide; 30
o
mL), pyridine (0.3 mL), and methanol (3 mL). The resulting solution was stirred at 70 C for 5
o
min, and then distributed to four 20 mL vials. The vials were then heated at 120 C in an
isothermal oven for 24 h. After cooling the vials to room temperature, the solid product was
removed by decanting with mother liquor and washed in DMF (3 x 10 mL) for 3 days. Solvent
exchange was carried out with methanol (3 x 10 mL) at room temperature for 3 days. The
o
material was then evacuated under vacuum at 140 C for 6 h, yielding 0.103 g of
Cu (BPDC) (BPY) in the form of blue crystals (67.5% based on copper nitrate).
2
2
2
.3. Catalytic studies
The Cu (BPDC) (BPY) was used as a catalyst for the copper-catalyzed coupling of benzoxazole
2
2
and aryl halides to achieve phenylbenzoxazole derivatives. In a typical experiment, a pre-
determined amount of Cu (BPDC) (BPY) was added to the flask containing a solution of
2
2
5
Page 5 of 35

iodobenzene (0.112 mL, 1 mmol), benzoxazole (0.238 g, 2 mmol), K PO (0.532 g, 2 mmol) and
3
4
n-hexadecane (0.1 mL) as internal standard in DMF (4 mL). The catalyst concentration was
calculated based on the molar ratio of copper/iodobenzene. The reaction mixture was stirred at
o
1
00 C under an argon atmosphere for 180 min. The reaction conversion was monitored by
withdrawing aliquots from the reaction mixture at different time intervals, quenching with an
aqueous NaOH solution (5%, 1 mL), drying over anhydrous Na SO , analyzing by GC with
2
4
reference to n-hexadecane, and further confirming product identity by GC-MS. To investigate
the recyclability of Cu (BPDC) (BPY), the catalyst was filtered from the reaction mixture after
2
2
the experiment, washed with copious amounts of DMF, dried under air at room temperature for 1
h, and reused if necessary. For the leaching test, a catalytic reaction was stopped after 30 min,
analyzed by GC, and filtered to remove the solid catalyst. The reaction solution was then stirred
for a further 150 min. Reaction progress, if any, was monitored by GC as previously described.
3
. Results and discussion
X
O
N
Cu (BPDC) (BPY)
O
N
2
2
+
R
DMF
R
X: -I,Br, Cl
R: -H, NO , COCH , CH , OCH , NH , CN, OH
2
3
3
3
2
Scheme 1. Direct C-H arylation reactions between benzoxazole and aryl halides using
Cu (BPDC) (BPY) catalyst.
2
2
In this work, the Cu (BPDC) (BPY) was synthesized in a yield of 67.5% by a solvothermal
2
2
method, according to a modified literature procedure [46]. The material was then characterized
6
Page 6 of 35

by several techniques, including XRD, SEM, TEM, TGA, FT-IR, AAS, H -TPR, and nitrogen
2
physisorption measurements (Fig. S7 – Fig. S18 in supporting information). The
Cu (BPDC) (BPY) was assessed for its catalytic activity in the direct heterocycle C-H arylation
2
2
by studying the coupling of iodobenzene and benzoxazole to form 2-phenylbenzoxazole as the
principal product (Scheme 1). Initial studies addressed the effect of temperature on the reaction
conversion, having carried out the arylation reaction in DMF at 7.5 mol% of catalyst, with the
iodobenzene:benzoxazole molar ratio of 1:2, in the presence of two equivalents of K PO base, at
3
4
o
o
o
1
00 C, 110 C, and 120 C, respectively. Aliquots were withdrawn from the reaction mixture at
different time intervals and analyzed by GC, giving kinetic data during the course of the reaction.
o
It was observed that the reaction carried out at 120 C could afford 95% conversion after 180
min. Decreasing the reaction temperature resulted in a significant drop in the reaction rate, with
o
o
5
6% and 44% conversions being detected for the reaction carried out at 110 C and 100 C,
respectively (Fig. 1). Daugulis and Do previously reported that the CuI-catalyzed direct
heterocycle C-H arylation reaction between benzoxazole and iodobenzene could proceed readily
o
o
at 140 C within 10 min [16]. The reaction temperature could be up to 160 C as previously
demonstrated by Miura and co-workers [2]. In the first example of the heterogeneous C-H
arylation between benzoxazole and iodobenzene using CuO nanoparticles as the catalyst, the
o
reaction was also carried out at 160 C for 180 min [19]. Moreover, it was observed that the
iodobenzene:benzoxazole molar ratio also exhibited a profound effect on the C-H arylation
o
reaction, having carried out the reaction in DMF at 120 C, in the presence of two equivalents of
K PO as the base, at 7.5 mol% of catalyst, with the reagent molar ratio of 1:2, 1:1.5, and 1:1,
3
4
respectively. Using less than two equivalents of benzoxazole led to a significant drop in the
7
Page 7 of 35

reaction conversion (Fig. 2). Indeed, two [2, 19] or three [16] equivalents of benzoxazole were
previously employed in the same reaction using CuI or CuO nanoparticles as the catalyst.
100
80
60
40
20
0
1
00 oC
110 oC
120 oC
0
30
60
90
120
150
180
Time (min.)
Fig. 1. Effect of temperature on reaction conversion.
100
80
60
40
20
0
1
1
1
:2
:1.5
:1
0
30
60
90
120
150
180
Time (h)
Fig. 2. Effect of reagent molar ratio on reaction conversion.
8
Page 8 of 35

100
80
60
40
20
0
0 mol%
3
5
mol%
mol%
7.5 mol%
0
30
60
90
120
150
180
Time (min.)
Fig. 3. Effect of catalyst concentration on reaction conversion.
Another factor that should be taken into accounts for the Cu (BPDC) (BPY)-catalyzed direct
2
2
heterocycle C-H arylation reaction between benzoxazole and iodobenzene is the catalyst
concentration. In the first example of the copper-catalyzed direct heterocycle C-H arylation
reaction between benzoxazole and iodobenzene, 10 mol% CuI was employed [16]. Similarly,
Miura and co-workers carried out the reaction using 10 mol% CuI as catalyst in the presence of
2
0 mol% triphenylphosphine as the ligand [2]. Moreover, up to 10 mol% CuO nanoparticles as
catalyst was also used for the same reaction [19]. It should be noted that the copper catalyst
concentration could be reduced to 1 mol% in the presence of 0.25 mol% palladium as co-catalyst
[47]. It was therefore decided to investigate the effect of catalyst concentration on the reaction
o
conversion. The arylation reaction was carried out in DMF at 120 C, with the
iodobenzene:benzoxazole molar ratio of 1:2, in the presence of two equivalents of K PO base, at
3
4
3
mol%, 5 mol%, and 7.5 mol% of catalyst, respectively. It was found that the coupling reaction
9
Page 9 of 35

of benzoxazole and iodobenzene could proceed readily in the presence of less than 10 mol%
Cu (BPDC) (BPY) catalyst. The reaction using 7.5 mol% of Cu (BPDC) (BPY) could afford
2
2
2
2
9
5% conversion after 180 min. Decreasing the catalyst concentration to 5 mol% resulted in a
significant drop in the reaction rate, with 55% conversion being observed after 180 min.
Furthermore, a conversion of only 19% was detected after 180 min in the presence of 3 mol%
catalyst. It should be noted that almost no reaction occurred in the absence of the
Cu (BPDC) (BPY), confirming the necessity of using the Cu-MOF as catalyst for the direct
2
2
heterocycle C-H arylation reaction (Fig. 3).
With these results in mind, we then decided to carry out the leaching test for the
Cu (BPDC) (BPY)-catalyzed direct heterocycle C-H arylation reaction between benzoxazole and
2
2
iodobenzene. Indeed, for liquid-phase organic reaction, the fact that some of catalytically active
species on the solid catalyst could migrate into the solution during the course of the reaction
might be a serious problem, and should be carefully addressed. Although the solid catalyst was
employed, the transformation might not proceed under real heterogeneous catalysis condition
[48]. In order to demonstrate if active copper species dissolved from the solid Cu-MOF catalyst
contribute to the total conversion of the direct heterocycle C-H arylation reaction, a control
experiment was carried out using a simple centrifugation during the course of the reaction.
Apparently, if the reaction still proceeded to higher conversion after the solid catalyst was
separated from the reaction mixture, this behavior would indicate that the reaction would not
occur under real heterogeneous catalysis condition. The coupling reaction was then carried out in
o
DMF at 120 C, using 7.5 mol% of catalyst, in the presence of two equivalents of K PO base,
3
4
with the iodobenzene:benzoxazole molar ratio of 1:2. The Cu (BPDC) (BPY) catalyst was
2
2
1
0
Page 10 of 35

removed from the reaction mixture after 30 min reaction time by simple centrifugation. The
liquid phase was then transferred to a new reactor vessel, and stirred for an additional 150 min at
o
1
20 C with aliquots being sampled at different time intervals, and analyzed by GC. It was found
that no further conversion was observed after the Cu (BPDC) (BPY) catalyst was separated from
2
2
the reaction mixture (Fig. 4). These observation would indicate that C-H direct functionalization
of benzoxazole by iodobenzene could only proceed in the presence of the solid
Cu (BPDC) (BPY) catalyst, and there should be no contribution to the total reaction conversion
2
2
from catalytically active copper species soluble in the liquid phase.
Fig. 4. Leaching test indicated no contribution from homogeneous catalysis of active species
leaching into reaction solution.
1
1
Page 11 of 35

Fig. 5. Effect of different bases on reaction conversion.
As for other direct heterocycle C-H arylation reaction, the presence of at least one equivalent of a
base should be required to accelerate the generation of intermediate organocopper species in the
catalytic cycle. In their pioneering work, Daugulis and Do demonstrated that best results could
be achieved by using lithium or potassium tert-butoxides as the base for the arylation reaction
between benzoxazole and iodobenzene [16]. Miura and co-workers employed less expensive,
mild inorganic bases, such as Na CO and K PO , in combination with triphenylphosphine as the
2
3
3
4
ligand for the same reaction [2]. Moreover, Zhang and co-workers investigated a series of
different bases for the arylation reaction using CuO nanoparticles as catalyst, and pointed out
that a more environmentally friendly mild base like K CO could be used instead of lithium or
2
3
potassium tert-butoxide [19]. Similarly, You and co-workers also reported that the CuI-catalyzed
1
2
Page 12 of 35

direct C-arylation of heteroaromatic compounds could proceed readily in the presence of K PO4
3
as the base [17]. It was therefore decided to investigate the effect of different bases on the
t
reaction conversion, using KO Bu, K CO , Na CO , CH COONa, K PO , triethylamine,
2
3
2
3
3
3
4
o
DABCO, respectively. The arylation reaction was carried out in DMF at 120 C, with the
iodobenzene:benzoxazole molar ratio of 1:2, in the presence of two equivalents of the base, at
7
.5 mol% of catalyst. It was found that Na CO , CH COONa, triethylamine, and DABCO were
2 3 3
unsuitable for the reaction, with less than 10% conversion being observed after 180 min. The
reaction using K CO as the base also occurred with difficulty, affording 25% conversion after
2
3
t
1
80 min. Interesting, strong base like KO Bu was also found to be ineffective for the reaction,
though a conversion of 52% was obtained after 180 min. Among these bases, K PO exhibited
3
4
the best performance, in which the arylation reaction could proceed to 95% conversion after 180
min (Fig. 5).
DMF
NMP
DMSO
DMAc
p-xylene
n-butanol
100
80
60
40
20
0
0
30
60
90
120
150
180
Time (min.)
Fig. 6. Effect of different solvents on reaction conversion.
1
3
Page 13 of 35

For liquid-phase organic transformations, solvents could have a profound effect on the reaction
rate, depending on the nature of the catalyst [48, 49]. In the first example of the heterogeneous
C-H arylation reaction between benzoxazole and iodobenzene using CuO nanoparticles as the
catalyst, Zhang and co-workers demonstrated that diglyme (diethylene glycol dimethyl ether)
offered better performance than others solvents such as DMSO, DMF, NMP, toluene, and
dioxane [19]. However, Daugulis [16], Miura [2] and co-workers successfully carried out the
same reaction using CuI as the catalyst in DMF. You and co-workers reported that the CuI-
catalyzed direct C-arylation of heteroaromatic compounds afforded best results in the mixture of
DMF:xylene (1:1 by volume) [17]. It was therefore decided to investigate the effect of different
solvents on the reaction conversion, having used DMF, DMSO, DMAc, NMP, p-xylene, and n-
butanol, respectively, as the reaction solvent. The C-H arylation reaction between benzoxazole
o
and iodobenzene was carried out at 120 C, with the iodobenzene:benzoxazole molar ratio of 1:2,
in the presence of two equivalents of K PO as the base, at 7.5 mol% of Cu (BPDC) (BPY)
3
4
2
2
catalyst. It was found that p-xylene was ineffective for the reaction, with only 6% conversion
being detected after 180 min. DMAc and n-butanol were also not suitable as solvent for the
reaction, though 36% and 69% were still observed after 180 min, respectively. The value could
be improved to 88% and 95% for the reaction carried out in NMP and DMF, respectively.
Among these solvents, DMSO exhibited the best performance, in which the reaction could
proceed to completion after 90 min (Fig. 6).
To clarify the advantages of employing the Cu (BPDC) (BPY) as catalyst for the direct
2
2
heterocycle C-H arylation reaction, the catalytic activity of the Cu-MOF was compared with that
of common copper salts, including Cu(NO ) , CuCl, CuCl , and CuI. Indeed, in the first example
3
2
2
1
4
Page 14 of 35

of the copper-catalyzed direct heterocycle C-H arylation reaction between benzoxazole and
iodobenzene, CuI was employed as an efficient homogeneous catalyst [16]. Miura and co-
workers also carried out the same reaction in the presence of CuI as the catalyst and
triphenylphosphine as the ligand [2]. Similarly, You and co-workers successfully carried out the
C-H arylation reaction between several heterocycles with aryl bromides using CuI as the catalyst
in conjunction with 1,10-phenanthroline as ligand [17]. The C-H arylation reaction was then
o
carried out at 120 C in DMSO, with iodobenzene:benzoxazole molar ratio of 1:2, in the
presence of two equivalents of K PO as the base, with 7.5 mol% of copper catalyst. It was found
3
4
that the CuI-catalyzed coupling reaction could afford 80% conversion after 180 min. CuCl
exhibited similar activity for the coupling reaction, with 77% conversion being achieved after
1
80 min. CuCl was found to offer lower catalytic activity than that of CuI in the C-H arylation
2
reaction, affording 54% conversion after 180 min. However, experimental results showed that
Cu(NO ) should not be used for the reaction, with only 15% conversion being detected after 180
3
2
min (Fig. 7). Interestingly, it was observed that the Cu (BPDC) (BPY) exhibited significantly
2
2
higher activity than that of these copper salts in this coupling reaction, indicating the superior
performance of the Cu-MOF as catalyst in the C-H direct functionalization of azoles by aryl
halides. Cu (BPDC) (BPY) possesses two rigid dicarboxylate along with a π-electron donor
2
2
bipyridine ligands. These ligands are known to stabilize the high valent copper complexes [50].
Compared to other common copper salts, Cu (BPDC) (BPY) exhibited significantly higher
2
2
activity due to the support of these ligands in the molecule. In addition, it can not be excluded
that the proximity of metal active sites in Cu (BPDC) (BPY) can also facilitate the reductive
2
2
elimination in the the bimetallic fashion [51]
1
5
Page 15 of 35

Fig. 7. Effect of different copper salts on reaction conversion.
To further emphasize the advantages of the Cu (BPDC) (BPY) as catalyst for the C-H direct
2
2
arylation of benzoxazole with iodobenzene, the catalytic activity of the Cu (BPDC) (BPY) was
2
2
also compared with that of other Cu-MOFs including Cu (BTC) , Cu(BDC), Cu(BPDC), and
3
2
Cu (BDC) (BPY). The synthesis procedures and XRD patterns (Fig. S9) of these Cu-MOFs are
2
2
mentioned in the supporting information. The coupling reaction was carried out in DMSO at 120
o
C, using 7.5 mol% of copper catalyst, in the presence of two equivalents of K PO as the base,
3
4
with the iodobenzene:benzoxazole molar ratio of 1:2. It was found that the C-H direct arylation
using the well-known Cu (BTC) as catalyst could proceed to 79% conversion after 180 min.
3
2
Indeed, this Cu-MOF previously exhibited high activity in several copper-catalyzed organic
transformations [36, 52-58]. It was observed that the C-H direct arylation reaction using the
1
6
Page 16 of 35

Cu(BDC) as catalyst occurred with slower rate, affording 67% conversion after 180 min. The
Cu(BPDC) was found to be almost unactive for the C-H direct arylation, with only 11%
conversion being observed after 180 min. It should be noted that the Cu (BPDC) (BPY)-
2
2
catalyzed C-H direct arylation of benzoxazole with iodobenzene could proceed to completion
after 90 min (Fig. 8). The fact that a remarkable difference in the catalytic activity between the
Cu (BPDC) (BPY) and the Cu(BPDC) was observed in the copper-catalyzed coupling reaction
2
2
indicated the important role of the linker 4,4’-bipyridine in preventing the formation of
catalytically inactive compact structure in the Cu-MOF [57].
In order to examine if the reaction occurred only on the external surface or also in internal pore
structure of the Cu (BPDC) (BPY), a control experiment was carried out employing
2
2
Cu (BDC) (BPY) as catalyst. Recently, Matsuoka and co-workers reported that the larger pore
2
2
size of M-MOFs (M = Mo or Cr) using biphenylene rings as organic linkers instead of phenylene
rings could result in higher catalytic activity due to the easier substance diffusion [59]. Indeed,
similar results was observed in our study, in which the coupling reaction using Cu (BDC) (BPY)
2
2
as the catalyst occurred with difficulty, affording only 52% conversion after 180 min (Fig. 8).
This behavior would support the assumption that there should be also contribution from
catalytically active sites located in internal pore structure of the Cu (BPDC) (BPY). Moreover,
2
2
to confirm the role of the copper sites on the Cu (BPDC) (BPY) in the C-H direct arylation
2
2
reaction of benzoxazole with iodobenzene, the effect of 2,2’-bipyridine and triphenylphosphine
as catalyst poison [60] on the reaction conversion was also investigated. The reaction was carried
o
out in DMSO at 120 C, using 7.5 mol% of Cu (BPDC) (BPY), with the
2
2
iodobenzene:benzoxazole molar ratio of 1:2, in the presence of two equivalents of K PO as the
3
4
1
7
Page 17 of 35

base and 15 mol% of catalyst poison. As expected, it was found that the reaction rate decreased
significantly, with 68% and 47% conversions being detected after 180 min in the presence of
triphenylphosphine and 2,2’-bipyridine, respectively (Fig. 9). Indeed, it was observed that the
XRD patterns of the Cu (BPDC) (BPY) changed slightly upon the adsorption of the catalyst
2
2
poison (Fig. S16). Moreover, FT-IR spectra of the 2,2’-bipirydine-adsorbed (Fig. S17) and
triphenylphosphine-adsorbed (Fig. S19) Cu (BPDC) (BPY) also exhibited a difference as
2
2
compared to those of the fresh Cu-MOF.
Fig. 8. Effect of different Cu-MOFs as catalyst on reaction conversion.
1
8
Page 18 of 35

Fig. 9. Effect of 2,2’-bipyridine and triphenylphosphine as catalyst poison on reaction
conversion.
From the view of green chemistry, the ability to recover and reuse the solid catalyst should be
taken into consideration. It is expected that the solid catalyst can be recovered and reused several
times before it eventually deactivates completely. The Cu (BPDC) (BPY) catalyst was therefore
2
2
investigated for recoverability and reusability in the C-H direct arylation of benzoxazole with
iodobenzene over six successive runs, by repeatedly separating the Cu (BPDC) (BPY) catalyst
2
2
from the reaction mixture after the reaction, washing it and then reusing it. The C-H arylation
o
reaction was carried out in DMSO at 120 C, employing 7.5 mol% of Cu-MOF catalyst, with the
iodobenzene:benzoxazole molar ratio of 1:2, in the presence of two equivalents of K PO as the
3
4
base. After the reaction was complete, the Cu (BPDC) (BPY) catalyst was separated from the
2
2
reaction mixture by simple centrifugation, then washed with copious amounts of DMF to remove
any physisorbed reagents, and dried at room temperature under vacuum for 1 h. It was found that
1
9
Page 19 of 35

the Cu (BPDC) (BPY) catalyst could be reused several times for the direct heterocycle C-H
2
2
arylation reaction between benzoxazole and iodobenzene without a significant degradation in
th
catalytic activity. Indeed, a conversion of more than 84% was still achieved in the 6 run (Fig.
1
0). In order to further examine the recoverability and reusability of the Cu (BPDC) (BPY) in
2 2
this reaction, the recovered Cu (BPDC) (BPY) catalyst was also characterized by FT-IR and
2
2
XRD. The FT-IR spectra of the reused Cu-MOF exhibited a similar absorption as compared to
those of the fresh catalyst (Fig. 11). The XRD result of the recovered Cu (BPDC) (BPY)
2
2
revealed that the crystallinity of the Cu-MOF catalyst was maintained though slight differences
in the diffractogram was observed (Fig. 12). These observations showed that the
Cu (BPDC) (BPY) could offer excellent reusability in the direct heterocycle C-H arylation
2
2
reaction between benzoxazole and iodobenzene, thus offering a route to green chemistry for this
transformation.
100
80
60
40
20
0
1
2
3
4
5
6
Run
Fig. 10. Catalyst recycling studies.
2
0
Page 20 of 35

Fig. 11. FT-IR spectra of the fresh (a) and reused (b) Cu (BPDC) (BPY) catalyst.
2
2
Fig. 12. X-ray powder diffractograms of the fresh (a) and reused (b) Cu (BPDC) (BPY) catalyst.
2
2
2
1
Page 21 of 35

The study was then extended to the direct heterocycle C-H arylation reaction between
benzoxazole and different aryl iodides, including iodobenzene, 4’-iodoacetophenone, 4-
nitroiodobenzene, 4-iodotoluene, 4-iodoanisole, and 4-iodoaniline, respectively (Table 1). .
o
Several reactions were carried out in DMSO at 120 C, with the aryl iodide:benzoxazole molar
ratio of 1:2, in the presence of two equivalents of K PO as the base, at 7.5 mol% of
3
4
Cu (BPDC) (BPY) catalyst. It was observed that the iodobenzene structure containing either an
2
2
electron-donating or an electron-withdrawing substituent slowed down the arylation, as
compared to the reaction between benzoxazole and iodobenzene. Indeed, Daugulis [16], Zhang
[19] and co-workers also reported similar observation, where iodobenzene was slightly more
reactive than its derivatives. With para-substituted iodobenzenes, the presence of an electron-
withdrawing group led to significantly higher reaction conversion than the case of an electron-
donating group. Indeed, the reaction of 4’-iodoacetophenone or 4-nitroiodobenzene with
benzoxazole afforded 90% and 93% conversions after 180 min, respectively. As expected, 4-
iodotoluene, 4-iodoanisole, and 4-iodoaniline were found to be less reactive in the arylation
reaction with benzoxazole (Fig. 13).. It was observed that the reaction of 4-iodotoluene and 4-
iodoanisole with benzoxazole afforded 63% and 46% conversions after 180 min, respectively.
2
2
Page 22 of 35

a
Table 1. Arylation scope with respect to aryl halides
O
N
X
O
N
Cu (BPDC) (BPY) (7.5 %)
2
2
R
K PO (2 equiv.)
R
3
4
o
X = I, Br, Cl
DMSO, t C
b
Entry
1
Aryl halide
Product
Convesion (%)
X =I, 95
X
O
=
=
Br, 91
Cl, 35
N
2
3
4
X
O
N
O
N
X =I, 63
Me
=
Br, 94 (82)
Me
X
X =I, 46
OMe
=
Br, 81
MeO
X
O
N
Me
O
X =I, 90
=Br, 96
=Cl, 99
X =I, 93
Me
O
5
X
O
N
NO2
=
=
Br, 99
Cl, 80
O N
2
6
7
8
Br
Cl
O
N
O
N
CN
OH
9
8 (74)
NC
HO
5
Br
2
O N
O
N
65
NO2
Br
9
MeO
O
N
36
OMe
2
3
Page 23 of 35

1
0
1
O N
Br
Br
NO
2
2
O
N
97
1
MeO
OMe
O
N
55 (45)
a
o
Aryl halide (2.0 equiv), benzoxazole (1 equiv), 1.0 mmol scale, 120 C; all reactions of aryl
o
bromides and aryl chlorides at 140 C; reactions of o- and m-substituents aryl bromides using 3.5
b
equiv of K PO GC conversions. Numbers in parentheses were isolated yields.
3
4.
The Cu (BPDC) (BPY)-catalyzed direct heterocycle C-H arylation reaction between
2
2
benzoxazole with different aryl bromides was also investigated. The reason for this trend is that
aryl bromides are normally less expensive, and hence more desirable as starting materials than
aryl iodides [61]. Daugulis [16], Miura [2] and co-workers previously reported the arylation
reaction between benzoxazole with different aryl iodides using CuI catalyst, and demonstrated
that the system was not effective with aryl bromides. You and co-workers expanded the protocol
to the C-H arylation reaction between a relatively wide range of heterocycles with different aryl
bromides using CuI as the catalyst and 1,10-phenanthroline as the ligand [17]. It was therefore
decided to investigate the Cu (BPDC) (BPY)-catalyzed arylation reaction between benzoxazole
2
2
and different aryl bromides, including 4-bromonitrobenzene, 4’-bromoacetophenone, 4-
bromobenzonitrile, bromobenzene, 4-bromotoluene, 4-bromoanisole, and 4-bromoaniline,
o
respectively. The reaction was carried out in DMSO at 120 C, with the aryl
bromide:benzoxazole molar ratio of 1:2, in the presence of two equivalents of K PO as the base,
3
4
at 7.5 mol% of Cu (BPDC) (BPY) catalyst. It was observed that the reaction proceeded with
2
2
o
difficulty at 120 C and only trace amount of 2-(4-nitrophenyl) benzoxazole was detected for the
o
reaction of 4-bromonitrobenzene. The reaction was then carried out at 140 C to accelerate the
2
4
Page 24 of 35

reaction rate. It was found that the reaction of 4-bromonitrobenzene and benzoxazole could
afford more than 99% conversion after 90 min. Moreover, the reaction of 4’-
bromoacetophenone, 4-bromobenzonitrile, bromobenzene, 4-bromotoluene, 4-bromoanisole, and
4
-bromoaniline occurred readily under this condition, with 96%, 98%, 91%, 94%, 81%, and 81%
conversions, respectively, being achieved after 180 min (Table 1). Arylation by aryl bromides
possessing electron-withdrawing group (nitro group) and electron-donating group (methoxy
group) at ortho and meta position was also possible (entry 8-11). Due to the steric and electronic
effects, greater amount of K PO were needed to obtained reasonable conversions. In particular,
3
4
aryl bromides with methoxy group are less active than aryl bromide, which is less reactive than
electron-deficient aryl bromides.
Aryl chlorides have been rarely reported as suitable reagents in C-H functionalization, though
these compounds are usually cheaper and more available than the corresponding aryl bromides
and aryl iodides [62]. Itami and co-workers previously demonstrated the first example of the C-H
direct activation of azoles by aryl chlorides, in which 2-phenyl benzothiazole derivatives were
synthesized successfully by employing Ni(OAc) as catalyst in conjunction with 1,1'-
2
t
o
bis(diphenylphosphino)ferrocene as ligand and BuOLi as the base at 140 C in dioxane [63]. It
was therefore decided to investigate the effect of different aryl chlorides, including 4-
chlorophenol, chlorobenzene, 4-chloronitrobenzene, and 4’-chloroacetophenone, respectively, on
the direct heterocycle C-H arylation using the Cu (BPDC) (BPY) catalyst. The reaction was
2
2
o
carried out in DMSO at 140 C, with the aryl chloride:benzoxazole molar ratio of 1:2, in the
presence of two equivalents of K PO as the base, at 7.5 mol% of catalyst. It was observed that
3
4
electron-deficient aryl chlorides exhibited better performance in the Cu (BPDC) (BPY)-
2
2
2
5
Page 25 of 35

catalyzed C-H functionalization. The direct heterocycle C-H arylation reaction between
benzoxazole with 4’-chloroacetophenone proceeded readily to completion after 60 min. 4-
Chloronitrobenzene was also reactive in the coupling reaction with benzoxazole using the
Cu (BPDC) (BPY) catalyst, with 80% conversion being achieved after 180 min. Unfortunately,
2
2
electron-rich aryl chlorides were found to offer low reactivity in the copper-catalyzed C-H
coupling reaction with benzoxazole. The reaction of benzoxazole with chlorobenzene and 4-
chlorophenol afforded 34% and 5% conversions after 180 min, respectively (Table 1).
Table 2. Arylation scope with respect to heterocycles
I
Heterocycle
Cu (BPDC) (BPY) (7.5 %)
2
2
Heterocycle
t
LiO Bu (3.5 equiv.)
o
DMF, 120 C
a
Entry
1
Heterocycle
Product
Convesion (%)
80 (71)
S
S
N
N
2
Me
S
Me
Cl
32
S
N
N
3
4
39 (33)
46 (42)
S
S
Cl
Me
N
Me
N
N
N
o
a
Phenyl iodide (2.0 equiv), heterocycles (1 equiv), 1.0 mmol scale, 120 C GC conversions
Number in parentheses were isolated yield.
To expand the generality of our conditions, arylation of several other heterocycles including
benzothiazole, 2-chlorothiophen, 4-methylthiazole, and N-methylbenzimidazole was conducted.
2
6
Page 26 of 35

The results showed that good conversions were obtained under modified conditions. For less
acidic heterocycles, lithium tert-butoxide was used instead of K PO . These results were
3
4
summarized in Table 2. Arylation proceeded at the most acidic C-H bond. Benzothioazole was
arylated at C2 position in 80 % conversions. Moderate conversions, 32 %, 39 %, and 46 % were
achieved for arylation of 4-methylthiazole, 2-chlorothiophene, and N-methylbenzimidazole,
respectively.
4
. Conclusions
In summary, the metal-organic framework Cu (BPDC) (BPY) was synthesized and characterized
2
2
by several techniques including XRD, SEM, TEM, FT-IR, TGA, AAS, H -TPR, and nitrogen
2
physisorption measurements. The Cu (BPDC) (BPY) exhibited high catalytic activity in direct
2
2
heterocycle C-H arylation using aryl halides as coupling partners. Excellent conversions were
obtained in the presence of a catalytic amount of the Cu-MOF. The Cu (BPDC) (BPY)-catalyzed
2
2
C-H arylation reaction could proceed to higher conversion than that of the reaction using
Cu (BTC) , Cu(BDC), Cu(BPDC), and Cu (BDC) (BPY) catalyst. Furthermore, under our
3
2
2
2
conditions, the Cu (BPDC) (BPY) also exhibited significantly higher activity than that of
2
2
common copper salts, including Cu(NO ) , CuCl, CuCl , and CuI. The C-H arylation reaction
3
2
2
could only proceed in the presence of the solid Cu-MOF catalyst, and there was no contribution
from leached active sites present in the solution. Excellent reusability of the Cu-MOF in the
direct heterocycle C-H arylation reactions was achieved, thus offering a route to more
environmentally benign method for this transformation.
2
7
Page 27 of 35

Acknowledgements
The Viet Nam National Foundation for Science and Technology Development - NAFOSTED is
acknowledged for financial support through project code 104.99-2012.25.
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