Ligand-free N-arylation of heterocycles using metal-organic framework [Cu(INA)2] as an efficient heterogeneous catalyst

Article abstract of DOI:10.1039/c5ra24165k

A metal-organic framework [Cu(INA)₂] was synthesized and used as a heterogeneous catalyst for arylation of a wide range of N-H heterocycles and aryl halides under ligand-free conditions. The N-arylation reaction involved the use of 5 mol% Cu-MOF catalyst with K₃PO₄ or ^tBuOLi as the base in dimethylacetamide (DMA) solvent at 100 °C in 6 h. [Cu(INA)₂] exhibited higher catalytic activity for the N-arylation transformation than that of common homogeneous copper catalysts and other Cu-MOFs with unsaturated open metal sites such as Cu₂(BDC)₂(BPY), Cu₃(BTC)₂, and Cu₂(BDC)₂(DABCO). Interestingly, reaction conditions are compatible with a wide range of N-H heterocycles, functional groups, and aryl chlorides. A leaching test indicated no contribution of leached active species in the reaction filtrate. Furthermore, the [Cu(INA)₂] catalyst could be facilely separated from the reaction mixture and recovered and reused several times without a significant degradation in catalytic activity.

Full text of DOI:10.1039/c5ra24165k

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Ligand-free N-arylation of heterocycles using metal-organic framework [Cu(INA)2]
as an efficient heterogeneous catalyst
*
Thanh Truong*, Chi V. Nguyen, Ngoc T. Truong, Nam T. S. Phan
Department of Chemical Engineering, HCMC University of Technology, VNUꢀHCM,
2
68 Ly Thuong Kiet, District 10, Ho Chi Minh City, Viet Nam
*
Email: ptsnam@hcmut.edu.vn
tvthanh@hcmut.edu.vn
Ph: (+84 8) 38647256 ext. 5681
Fx: (+84 8) 38637504
Abstract
A metalꢀorganic framework [Cu(INA) ] was synthesized and used as a heterogeneous
2
catalyst for arylation of wide range of N-H heterocycles and aryl halides under ligand-
free conditions. The Nꢀarylation reaction involved the use of 5 mol% CuꢀMOF catalyst
t
o
with K PO or BuOLi as the base in dimethylacetamide (DMA) solvent at 100 C in 6 h.
3
4
The [Cu(INA) ] exhibited higher catalytic activity for the Nꢀarylation transformation than
2
that of common homogeneous copper catalysts and other CuꢀMOFs with unsaturated
open metal sites such as Cu (BDC) (BPY), Cu (BTC) , and Cu (BDC) (DABCO).
2
2
3
2
2
2
Interestingly, reaction conditions are compatible with wide range of N-H heterocycles,
functional groups, and aryl chlorides. Leaching test indicated no contribution of leached
active species in reaction filtrate. Furthermore, the [Cu(INA) ] catalyst could be facilely
2
separated from the reaction mixture and recovered and reused several times without a
significant degradation in catalytic activity.
Keywords: Metalꢀorganic framework; Nꢀarylation, N-H heterocycles; CꢀN coupling;
heterogeneous catalyst.
1

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1
. Introduction
NꢀArylated heterocycles have emerged as important intermediates commonly used in the
synthesis of many biologically active natural products, agrochemicals, and
pharmaceutical candidates as well as functional materials [1ꢀ3]. They have been
conventionally synthesized by the copperꢀcatalyzed Ullmannꢀtype transformation [4].
However, this protocol often required the presence of stoichiometric or even greater
quantities of copper salts at high temperatures, leading to the formation of large amounts
of hazardous copperꢀbased wastes [4, 5]. Several palladiumꢀcatalyzed CꢀN crossꢀ
coupling transformations of aryl halides with azoles in the presence of sterically hindered
phosphine ligands have been developed [6, 7]. Although high yields under relatively mild
conditions were achieved, using homogeneous phosphine palladium catalysts would
suffer a number of drawbacks, such as high cost, relatively rare availability, and tedious
workꢀup. Taillefer and coꢀworkers previously reported the Nꢀarylation of pyrazole using
Cu O and oximeꢀtype ligands as catalyst systems [8]. Hosseinzadeh and coꢀworkers
2
demonstrated that the Nꢀarylation of diazoles could be accomplished using CuI as catalyst
in the presence of 1,10ꢀphenanthroline as ligand [9]. Bolm and Correa developed the Nꢀ
arylation of pyrazole using FeCl in conjunction with N,N’ꢀdimethylethylenediamine as
3
catalyst system [10]. Several publications using copper heterogeneous catalytic systems
for this transformation have been disclosed [11ꢀ13]. Often, expensive Cs CO , long
2
3
reaction time, soluble ligands, or inert atmosphere was required. Furthermore, difficulty
in reusability or loss of activity was also observed [14]. Though our group has disclosed
the use of Cu (BDC) (DABCO) for Nꢀarylation, reaction conditions were only applicable
2
2
2

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to imidazoles [15]. The development of more environmentally benign and robust
heterogeneous protocols for the Nꢀarylation of heterocycles is still our primary concern in
the near future.
Metalꢀorganic frameworks (MOFs), also known as coordination polymers, have emerged
as a relatively new class of porous, crystalline materials constructed from metalꢀ
containing nodes and multidirectional organic linkers [16ꢀ18]. Due to their special
physical properties, MOFs have been considered as promising materials for potential
applications in gas storage media, separations, chemical sensors, thin film devices, optics,
drug carriers, biomedical imaging, and catalysis [19ꢀ27]. The application of MOFs in
catalysis has currently attracted significant attention from both academics and industry,
and relevant publications have increased significantly in the last few years [28ꢀ30].
Indeed, both carbonꢀcarbon [31ꢀ38] and carbonꢀheteroatom forming transformations
using MOFs as catalysts or catalyst supports have recently been explored [39ꢀ49]. There
should be no doubts that the catalysis application of MOFs will be expanded in the near
future. Among several kinds of MOFs as heterogeneous catalysts, copperꢀbased MOFs
could offer promising activity and selectivity for a variety of organic reactions due to
their unsaturated open copper metal sites [41, 50ꢀ57]. In this work, we present a
heterogeneous protocol for Nꢀarylation of wide range of heterocycles using the metalꢀ
organic framework [Cu(INA) ] as an efficient heterogeneous catalyst and inexpensive
2
K PO base under ligandꢀfree conditions. Under reported conditions, the [Cu(INA) ]
3
4
2
offered higher catalytic activity for the transformation than that of other CuꢀMOFs such
as Cu (BDC) (BPY), Cu (BTC) and Cu (BDC) (DABCO), and that of homogeneous
2
2
3
2
2
2
copper catalysts such as CuI, CuCl , Cu(NO ) , Cu(OAc) , and CuSO . Interestingly, the
2
3 2
2
4
3

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optimized conditions are applicable for aryl chlorides, which previously required
palladium catalysts or complicated ligands under copper catalysis.
2
. Experimental
2
.1. Materials and instrumentation
All reagents and starting materials were obtained commercially from SigmaꢀAldrich and
Merck, and were used as received without any further purification unless otherwise
noted. Nitrogen physisorption measurements were conducted using a Micromeritics 2020
volumetric adsorption analyzer system. Samples were pretreated by heating under
o
vacuum at 150 C for 3 h. A Netzsch Thermoanalyzer STA 409 was used for
o
thermogravimetric analysis (TGA) with a heating rate of 10 C/min under a nitrogen
atmosphere. Xꢀray 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 (INA) ] sample was
2
dispersed on holey carbon grids for TEM observation. Elemental analysis with atomic
absorption spectrophotometry (AAS) was performed on an AAꢀ6800 Shimadzu. Fourier
transform infrared (FTꢀIR) spectra were obtained on a Nicolet 6700 instrument, with
samples being dispersed on potassium bromide pallets.
Gas chromatographic (GC) analyses were performed using a Shimadzu GC 2010ꢀPlus
equipped with a flame ionization detector (FID) and an SPBꢀ5 column (length = 30 m,
inner diameter = 0.25 mm, and film thickness = 0.25 ꢁm). The temperature program for
4

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o
o
GC analysis held samples at 80 C for 1 min; heated them from 80 to 280 C at 35
o
o
C/min; held them at 280 C for 10 min. Inlet and detector temperatures were set constant
o
at 290 C. nꢀHexadecane was used as an internal standard to calculate reaction
conversions. GCꢀMS analyses were performed using a Hewlett Packard GCꢀMS 5972
with a RTXꢀ5MS column (length = 30 m, inner diameter = 0.25 mm, and film thickness =
o
0
.5 ꢁm). The temperature program for GCꢀMS analysis heated samples from 60 to 280 C
o
o
at 10 C/min and held them at 280 C for 10 min. Inlet temperature was set constant at
o
1
2
80 C. MS spectra were compared with the spectra gathered in the NIST library. The H
1
3
and C NMR were recorded in CDCl using residual solvent peak as a reference on a
3
Bruker spectrophotometer at 500 MHz and 125 MHz, respectively.
2
.2. Synthesis of the metal-organic framework [Cu(INA)2]
In a typical preparation, a mixture of Cu(NO ) .3H O (0.193 g; 0.8 mmol) in DMF (17.5
3
2
2
mL) and isonicotinic acid (INAH) (0.049 g; 0.4 mmol) in NMP (7 mL) was mixed, and
stirred for 5 min. Pyridine (1.5 mL) was then added, and the resulting solution was
o
distributed to ten 5 mL vials. The vials were then heated at 100 C in an isothermal oven
for 72 h. After cooling the vials to room temperature, the solid product was removed by
decanting with mother liquor and washed in DMF (3 x 20 mL) for 3 days. Solvent
exchange was carried out with DCM (3 x 20 mL) at room temperature. The material was
o
then evacuated under vacuum at 140 C for 3 h, yielding 0.032 g of [Cu(INA) ] in the
2
form of blue crystals (65 % based on isonicotinic acid).
2
.3. Catalytic studies
In a typical experiment, a mixture of 4ꢀiodoacetophenone (0.492 g, 2.0 mmol), pyrazole
0.272 g, 4.0 mmol), K PO as a base (0.848 g, 4.0 mmol), and nꢀhexandecane (0.15
(
3
4
5

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mL) as an internal standard in DMA (4 mL) was added into a 25 mL flask containing
the preꢀdetermining amount of [Cu(INA) ] catalyst. The catalyst amount was calculated
2
based on the molar ratio of copper/4ꢀiodoacetophenone. The reaction mixture was
o
magnetically stirred at 100 C for 6 h.
Reaction conversion was monitored by withdrawing aliquots from the reaction mixture at
different time intervals, quenching with aqueous KOH solution (1 %, 0.2 mL). The
organic components were then extracted into diethyl ether (2 mL), dried over anhydrous
Na SO , analyzed by GC with reference to nꢀhexadecane. The product identity was
2
4
further confirmed by GCꢀMS and NMR. To investigate the recyclability of the
[
Cu(INA) ], the catalyst was separated from the reaction mixture by simple
2
o
centrifugation, washed with copious amounts of DMF and DCM, dried 140 C under
vacuum in 2 h, and reused if necessary. For the leaching test, a catalytic reaction was
stopped after 1 h, analyzed by GC, and centrifuged to remove the solid catalyst. The
o
reaction solution was then stirred for a further 5 h at 120 C. Reaction progress, if any,
was monitored by GC as previously described.
3
. Results and discussion
The metalꢀorganic framework [Cu(INA) ] was synthesized according to a modified
2
literature procedure, and was characterized by several techniques, including XRD, SEM,
TEM, TGA, FTꢀIR, AAS, and nitrogen physisorption measurements (Fig. 1 and Fig. S7 –
Fig. S13). The analysis results were in good agreement with previous reports [58, 59].
Structurally, the building block unit of the framework is composed of Cu(II) squareꢀ
pyramidal geometry linked by five isonicotinate ligands while the carboxylate oxygen
atoms from the other two isonicotinate ligands occupy the rest of the two vertices [58ꢀ
6

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5
9]. We hypothesized that this structure would result in weak interaction between copper
centers within the network structure. Therefore, it is suitable for association/dissociation
in catalytic cycle. Furthermore, weak interaction also indicated the metalꢀmetal
interaction behavior [59]. It was recently reported that bimetallic copper center possessed
exceptionally strong activity toward cross coupling reactions [60]
Fig. 1. PXRD and TGA of synthesized [Cu(INA)2]
In optimization studies, the [Cu(INA) ] was used as catalyst for the Nꢀarylation of
2
heterocycles by 4ꢀiodoacetophenone (Scheme 1). Pyrazole was chosen due to its poor
activity toward arylation in reported procedures. Condition screening was initially
conducted with 5 mol% [Cu(INA) ] catalyst, 4ꢀiodoacetophenone: pyrazole molar ratio
2
of 1: 2, and inexpensive K PO base in DMF solvent.
3
4
[
Cu(INA)2]
NH
N
N
I
N
o
1
00 C, DMF
O
O
Scheme 1. The Nꢀarylation of pyrazole with 4ꢀiodoacetophenone using [Cu(INA)2]
catalyst.
7

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Fig. 2. Effect of temperature on reaction conversions.
Effect of temperature on reaction conversion was kinetically investigated (Fig. 2). It was
found that the [Cu(INA) ]ꢀcatalyzed Nꢀarylation reaction could proceed to 88%
2
o
conversion after 6 h at 100 C. Decreasing the temperature resulted in a significant drop
in the reaction rate, with 66% and 61% conversions being observed for the reaction
o
o
carried out at 90 C and 80 C, respectively. It should be noted that the Nꢀarylation
reaction could not occur at room temperature in the presence of [Cu(INA) ] catalyst, with
2
no trace amount of product being detected. Indeed, the Nꢀarylation of pyrazole was
o
previously carried out in the temperature range of 110 ꢀ 140 C under different catalysis
conditions [8ꢀ10, 61, 62].
8

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Fig. 3. Effect of reagent molar ratio on reaction conversion.
Fig. 4. Effect of catalyst amount on reaction conversion.
The effect of reagent molar ratio (pyrazole/4ꢀiodoacetophenone) on the reaction
conversion was investigated (Fig. 3). It was observed that using the molar ratio less than
1
.5 resulted in a drop in the reaction conversion, though 66% conversion was still
achieved for the reaction using 1.0 equivalents of pyrazole. With respect to catalyst
9

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loading, as expected, decreasing the catalyst concentration led to a dramatic drop in the
reaction rate, though 72% and 54% conversions were still achieved with 3 mol% and 1
mol% CuꢀMOF catalyst, respectively. It should be noted that almost no reaction occurred
in the absence of the [Cu(INA) ] catalyst, indicating the necessity of using the CuꢀMOF
2
as catalyst for the Nꢀarylation reaction (Fig. 4). In the first example of the ligandꢀfree Nꢀ
arylation reaction of pyrazole, Rao and coꢀworkers used 10 mol% graphiteꢀsupported iron
catalyst [61]. Other groups also employed 10 mol% catalyst for the same transformation,
though different ligands were required in the systems [8, 10, 62].
Fig. 5. Effect of solvent on reaction conversion.
In several cases, the solvent could dramatically accelerate or slow down the
transformation, depending on the nature of the catalyst material [63, 64]. Taillefer and
coꢀworkers previously carried out the Nꢀarylation of pyrazole with aryl or heteroaryl
bromides or iodides in toluene, DMF or acetonitrile using Cu O and oximeꢀtype ligands
2
as catalyst systems [8]. Bolm and Correa reported the FeCl ꢀcatalyzed Nꢀarylation of
3
1
0

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pyrazole carried out in toluene using N,N’ꢀdimethylethylenediamine as ligand [10].
Hosseinzadeh and coꢀworkers employed xylene as solvent for the CuIꢀcatalyzed Nꢀ
arylation of diazoles in the presence of 1,10ꢀphenanthroline as ligand [9]. Teo and coꢀ
workers performed the same reaction using MnCl2 catalyst with transꢀ1,2ꢀ
diaminocyclohexane as the assisting ligand in water [62]. In the first example of the
ligandꢀfree Nꢀarylation reaction of pyrazole using graphiteꢀsupported iron catalyst, Rao
and coꢀworkers carried out the reaction in DMSO [61]. Therefore, different solvents
including DMF, DMA, NMP, 1,4ꢀdioxane, oꢀxylene, and toluene were then examined
(
Fig. 5). It was found that the transformation proceeded with difficulty in oꢀxylene and
toluene, with only 28% and 19% conversions respectively. The reaction carried out in
,4ꢀdioxane afforded 46% conversion. Cyclic amide solvent NMP was also found to be
1
not effective. Noticeably, DMA was found to be optimal solvent with up to 92%
conversion was obtained.
Fig. 6. Effect of base on reaction conversion.
1
1

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0
.5 equiv
.5 equiv
1.5 equiv
no base
2
100
80
60
40
20
0
0
1
2
3
4
5
6
Time (h)
Fig. 7. Effect of various amount of K PO on reaction conversion.
3
4
Next, various common inorganic and organic bases were employed (Fig. 6). Particularly,
almost no reaction occurred in the absence of base indicating the .importance of the base
in the transformation. Both K CO and CH COONa were found to be unsuitable with
2
3
3
only 24% conversion. The Nꢀarylation reaction using CH ONa base afforded 41%
3
conversion while approximate 50 % conversion was obtained with NaOH. It was found
t
that both K PO and BuOLi could be used for the [Cu(INA) ]ꢀcatalyzed Nꢀarylation
3
4
2
reaction, with 92% and 94% conversions. From the industrial point of view, K PO
3
4
would be more commercially available and therefore should be used for the
transformation. Furthermore, investigation of using different amount of K PO confirmed
3
4
that 1.5 equivalent was optimal. In particular, reaction using more than 1.5 equivalent did
not significantly increase the reaction conversion while only 32 % was obtained when 0.5
equivalent of K PO was employed.
3
4
1
2

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Fig. 8. Different CuꢀMOFs as catalyst for the Nꢀarylation reaction.
To highlight the significant aspect of using the [Cu(INA) ] as catalyst for Nꢀarylation, the
2
catalytic activity of the [Cu(INA) ] was compared with that of other CuꢀMOFs which
2
previously reported to possess open metal sites and high catalytic activity toward cross
coupling reactions [65ꢀ74] (Fig. 8). Although MOFꢀ199 were commonly used as efficient
catalyst for several copperꢀcatalyzed organic transformations [64ꢀ71], this CuꢀMOF
offered significantly lower catalytic activity than the [Cu(INA) ]. The Nꢀarylation
2
reaction using Cu (BDC) (DABCO) catalyst also proceeded slowly, though 63%
2
2
conversion was still observed after 6 h. The reaction conversion could be improved to
5% when Cu (BDC) (BPY) catalyst was employed.
7
2
2
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3

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Fig 9. Comparison in catalytic activity of [Cu(INA) ] with several copper salts.
2
Despite the high thermal stability, low reactivity of heterogeneous catalysts was often
observed mainly due to their structural rigidity or loss of activation by the aggregation of
active species [75]. With exceptionally high surface area, semiꢀrigid properties, and no
metal aggregation, MOFs containing transition metals are expected to overcome these
major problems of solid catalysts while still maintain their beneficial properties in
handling and separation as compared to homogeneous counterparts. To further verify the
excellent catalytic activity of [Cu(INA) ], the catalytic performance of several
2
homogeneous copper salts was then investigated under optimal conditions (Fig. 9).
Interestingly, all of these tested copper salts were less active than the [Cu(INA) ] for the
2
Nꢀarylation reaction, though up to 75% conversion was still obtained after 6 h for the case
of CuI. It should be noted that isonicotinic acid exhibited no activity for the Nꢀarylation
reaction, with no trace amount of product being detected while Cu(NO ) cluster afforded
3
2
1
4

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only 65% conversion. These observation would imply that synergetic impact of linkers
on metal cluster would be of significant importance for the transformation, though further
studies would be necessary to elucidate the reaction mechanism of the [Cu(INA) ]ꢀ
2
catalyzed Nꢀarylation reaction.
Fig. 10. Leaching test indicated no contribution from homogeneous catalysis of active
species leaching into reaction solution.
In order to clarify if active copper species dissolved from the solid [Cu(INA) ] catalyst, if
2
any, could be active for the Nꢀarylation reaction, a control experiment was carried out
using a simple filtration during the course of the reaction. After 1 h with a conversion of
5
5% being observed, the [Cu(INA) ] catalyst was separated from the reaction mixture by
2
simple filtration. The liquid phase was then transferred to a new reactor vessel, and
o
magnetically stirred for an additional 5 h at 100 C with aliquots being sampled at
different time intervals. It was found that almost no further conversion was observed for
the Nꢀarylation reaction after the [Cu(INA) ] catalyst was removed (Fig. 10).
2
2
+
Furthermore, ICPꢀMS of reaction filtrate indicated the presence of <10 ppm of Cu .
1
5

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These observations would indicate that contribution from catalytically active species
soluble in the liquid phase is unlikely.
Fig. 11. Catalyst recycling studies.
The recoverability and reusability of the [Cu(INA) ] catalyst in the Nꢀarylation of
2
pyrazole with 4ꢀiodoacetophenone over five successive runs was studied by repeatedly
separating the CuꢀMOF catalyst from the reaction mixture. After each catalysis run, the
CuꢀMOF catalyst was filtered from the reaction mixture, washed with copious amounts
o
of DMA and DCM to remove any physisorbed reagents, dried at 140 C under vacuum in
2
h, then reused in further catalysis runs under identical conditions to those of the
previous experiment. It was found that the [Cu(INA) ] catalyst could be recovered and
2
reused several times in the Nꢀarylation reaction without a significant degradation in
th
catalytic activity. Indeed, a conversion of 84% was still achieved in the 5 run (Fig. 11).
The XRD result of the recovered [Cu(INA) ] revealed that the crystallinity of the Cuꢀ
2
MOF catalyst could be maintained, though slight difference in the diffractogram was
detected (Fig. 12). FTꢀIR spectra of the reused [Cu(INA) ] showed a similar absorption
2
1
6

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as compared to that of the fresh catalyst (Fig. 13) except the peak at about 1700 cmꢀ1. In
particular, within the Cu(INA) , the carboxylates tailing inside of the cavities are able to
2
interact with guest molecules. The absence of peak at about 1700 cmꢀ1 in reused
Cu(INA) could be rationalized by the interaction of carboxylate with solvent molecules.
2
Furthermore, N absorption/desorption examination of the used catalyst indicated that
2
only slight decrease in BET surface area was observed (Fig. S10).
Fig. 12. Xꢀray powder diffractograms of the fresh (a) and reused (b) [Cu(INA) ] catalyst.
2
1
20
(
(
a)
b)
8
4
0
0
0
3
500
3000
2500
2000
1500
1000
500
-1
Wavenumber (cm )
Fig. 13. FTꢀIR spectra of the fresh (a) and reused (b) [Cu(INA) ] catalyst.
2
1
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a
Table 1. Reaction scope with respect to coupling partners.
Entry
1
Iodides
Heterocycles
Products
Conversion (%)
O
N
O
94 (87)
I
N
N
I
NO2
2
N
NO2
90 (87)
N
X = I, 74
X = Cl, 52
3
4
N
N
X = I, 67
X = Cl, 41
N
N
b
5
I
O
N
O
54
4
6
N
b
I
NH
2
6
N
NH2
(95 %
selectivity)
b
7
77
N
O
X = Br, 86
X = Cl, 71 (67)
8
9
N
O
93 (90)
90
I
O
O
1
0
1
I
I
1
68
1
8

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O
12
91
I
O
O
1
3
4
98
I
I
1
89
a
b t
2
.0 mmol scale, DMA (4 mL), numbers in parenthesis indicated the isolated yields. BuOLi was
used.
The generality of optimized conditions was examined by using various aryl halides and
NꢀH heterocycles coupling counterparts (Table 1). With respect to aryl halides, excellent
reactions conversions were obtained with aryl iodides containing electronꢀwithdrawing
groups (entries 1, 2). Similar numbers between conversion and isolated yields indicated
the good selectivity under optimized conditions. In addition, good conversions were still
obtained with iodobenzene, 4ꢀiodoanisole, and 4ꢀiodotoluene (entries 3ꢀ5). Interestingly,
reaction is highly selective toward heterocyclic NꢀH and only trace amount of homoꢀ
coupling of 4ꢀiodoaniline was observed (entry 6). Monoꢀarylion using using 1,4ꢀ
diiodobenzene is possible and product was obtained in good yield (entry 7). Interestingly,
optimized conditions are also applicable for aryl bromides and aryl chlorides (entries 3, 4,
8
) It is worth mentioning that complex ligands were required for arylation using aryl
halides under homogeneous catalysis while all reported heterogeneous catalytic systems
were not effective when aryl chloride coupling partners were employed [11ꢀ15].
Furthermore, the optimized conditions are not limited to pyrazole. Specifically, arylation
of pyrrole, 3ꢀmethylindole, 6ꢀbromoindole, imidazole afforded products with excellent
conversions (entries 9ꢀ12). Amination by aliphatic cyclic NꢀHs such as morpholine and
pyrrolidine were also performed with high yields (entries 13, 14).
1
9

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Reaction mechanism was proposed in Scheme 2. In the presence of base, oxidative
addition of Cu complex with aryl halides was occurred. Interaction of N-H bonds with
copper halide intermediate (I) afforded copper complex (II) after elimination of HX.
Reductive elimination generated desired product and recovered copper complex back to
catalytic cycle. The exceptional catalytic activities of Cu(INA) toward Nꢀarylation could
2
be rationalized by: (1) synergetic effect of rigid linkers as coordinating ligands; (2)
bimetallic copper complexes; (3) strong coordination of N-H amines with copper
complex intermediates within the framework.
4
. Conclusions
In summary, the metalꢀorganic framework [Cu(INA) ] was solvothermaly synthesized
2
from the reaction of copper nitrate trihydrate and isonicotinic acid and characterized by
several techniques including XRD, SEM, TEM, FTꢀIR, TGA, AAS, and nitrogen
physisorption measurements. The [Cu(INA) ] was used as an efficient heterogeneous
2
catalyst for the Nꢀarylation of heterocycles under ligand-free conditions. Optimal
conditions involved the use of [Cu(INA) ] (5% mol), K PO base (2 equiv.) in DMA
2
3
4
2
0

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o
solvent at 100 C in 6h. Reaction conditions are compatible with wide range of N-H
heterocycles, functional groups, and aryl chlorides. Interestingly, the [Cu(INA) ] was
2
more catalytically active than common homogeneous copper catalysts such as CuI,
CuCl , Cu(NO ) , Cu(OAc) , and CuSO . The [Cu(INA) ] also exhibited higher catalytic
2
3 2
2
4
2
activity for the transformation than that of other CuꢀMOFs such as Cu (BDC) (BPY),
2
2
Cu (BTC) , and Cu (BDC) (DABCO). The reactions could only proceed in the presence
3
2
2
2
of the solid [Cu(INA) ] catalyst with no contribution from leached active copper species.
2
The [Cu(INA) ] catalyst could be facilely separated from the reaction mixture and
2
recovered and reused several times without a significant loss in catalytic activity.
Acknowledgements
Viet Nam National University HoChiMinh City (VNUꢀHCM) is acknowledged for
financial support through project code TX2015ꢀ20ꢀ05.
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Graphical abstract