A copper-based metal-organic framework as an efficient and reusable heterogeneous catalyst for ullmann and goldberg type C-N coupling reactions

Article abstract of DOI:10.3390/molecules201219756

A highly porous metal-organic framework (Cu-TDPAT), constructed from a paddle-wheel type dinuclear copper cluster and 2,4,6-tris(3,5-dicarboxylphenylamino)-1,3,5-triazine (H₆TDPAT), has been tested in Ullmann and Goldberg type C-N coupling reactions of a wide range of primary and secondary amines with halobenzenes, affording the corresponding N-arylation compounds in moderate to excellent yields. The Cu-TDPAT catalyst could be easily separated from the reaction mixtures by simple filtration, and could be reused at least five times without any significant degradation in catalytic activity.

Full text of DOI:10.3390/molecules201219756

Article
A Copper-Based Metal-Organic Framework as an
Efficient and Reusable Heterogeneous Catalyst for
Ullmann and Goldberg Type C–N Coupling Reactions
1
1,
1
2
1
1
Wei Long , Wenge Qiu *, Chongwei Guo , Chuanqiang Li , Liyun Song , Guangmei Bai ,
Guizhen Zhang 1 and Hong He *
1,
Received: 30 October 2015 ; Accepted: 17 November 2015 ; Published: 27 November 2015
Academic Editor: Maxim L. Kuznetsov
1
Beijing Key Laboratory for Green Catalysis and Separation, Department of Chemistry and Chemical
Engineering, College of Environmental and Energy Engineering, Beijing University of Technology,
Beijing 100124, China; longwei007@163.com (W.L.); gcwhome@emails.bjut.edu.cn (C.G.);
songly@bjut.edu.cn (L.S.); baiguangmei@bjut.edu.cn (G.B.); zhangguizhen@bjut.edu.cn (G.Z.)
2
Department of Applied Chemistry, College of Science, Chongqing Jiaotong University,
Chongqing 400074, China; lichuanqiang_cn@163.com
*
Correspondence: qiuwenge@bjut.edu.cn (W.Q.); hehong@bjut.edu.cn (H.H.);
Tel.: +86-10-157-1117-8438 (W.Q. & H.H.); Fax: +86-10-6739-1983 (W.Q. & H.H.)
Abstract: A highly porous metal-organic framework (Cu-TDPAT), constructed from a paddle-wheel
type dinuclear copper cluster and 2,4,6-tris(3,5-dicarboxylphenylamino)-1,3,5-triazine (H TDPAT),
6
has been tested in Ullmann and Goldberg type C–N coupling reactions of a wide range of primary
and secondary amines with halobenzenes, affording the corresponding N-arylation compounds in
moderate to excellent yields. The Cu-TDPAT catalyst could be easily separated from the reaction
mixtures by simple filtration, and could be reused at least five times without any significant
degradation in catalytic activity.
Keywords: metal-organic frameworks; C–N coupling; heterogeneous catalysis; copper complex
1
. Introduction
The N-aryl heterocycles are very important structural motifs in biological, pharmaceutical
and material science products [1–3]. Formation of C–N bonds by Ullmann and Goldberg
coupling reactions represents a powerful tool for the preparation of these nitrogen-containing
compounds on both laboratory and industrial scales [4–7]. However the classic Ullmann and
Goldberg coupling reactions suffer from drawbacks such as harsh reaction conditions, including
high reaction temperatures, extended reaction times, and the use of large amounts of copper.
Since two separate research groups achieved an important breakthrough with the discovery of
efficient copper/ligand systems that enable these cross coupling reactions to occur under much
milder conditions at the beginning of the 21st century [8,9], the formation of C–N bonds by
copper-mediated cross-coupling approaches has undergone a renaissance in the last decade [10–12].
Many classes of ligands, including diamines [4,13], amino acids [14–16], amino alcohols [17,18],
diols [19], diethylamine [20], diphosphines [21], phenanthrolines [22,23], pyridine N-oxide [24],
β-diketones [25–27] and metformin [28,29], have been used to promote the copper-catalyzed
cross-coupling C–N bond-forming reactions. Moreover, a few metal- and ligand-free [30–32],
and photoinduced [33–35] C–N coupling reactions have also been reported. Meanwhile, a few
mechanistic [36,37] and computational studies [38] have been conducted on these copper-mediated
cross-coupling reactions in order to understand these intriguing catalytic processes in detail.
Molecules 2015, 20, 21178–21192; doi:10.3390/molecules201219756
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Molecules 2015, 20, 21178–21192
Because of the increasing concern regarding environmental impact, the heterogeneous
catalysis has received much attention recently due to its advantages of ease of product separation,
catalyst recovery and recyclability. Several categories of copper-based heterogeneous catalysts for
the Ullmann and Goldberg coupling reactions, including copper compound nanoparticles [39–41],
inorganic materials (e.g., mesoporous nitrogen-doped carbon [42], SiO [43,44], fluoroapatite [45]
2
and Fe O [46,47])—supported catalytic systems, and organic polymer (e.g., polystyrene [48–50],
3
4
chitosan [51] and polytriallylamine [52])-supported catalytic systems, have been reported. In the past
decade, metal-organic frameworks (MOFs) have received much attention as catalytic materials in
addition to their applications in gas storage and separation due to their unique features, including
their crystallinity, porous structure, huge specific surface area and the high density of open metal sites
in the framework [53–55]. Several studies on the catalytic activity of MOFs with active open metal sites
have shown their potential applications in reactions like hydrogenation [56,57], isomerization [58],
cyanosilylation [59,60], oxidation [61–65], photocatalysis [66,67], Friedel-Crafts reaction [68–70], and
condensation reactions [71]. However, the Ullmann and Goldberg type C–O, C–N and C–S coupling
reactions over MOFs have barely been explored [72–75]. Cu-TDPAT [76] based on [Cu (COO) ]
2
4
square paddle-wheel secondary building units (SBUs) with rht-topology is highly porous, with a large
surface area and pore volume, and should be a good potential copper-based heterogeneous catalyst.
Herein, we report the applications of Cu-TDPAT as an efficient and reusable heterogeneous catalyst
for Ullmann and Goldberg type C–N coupling reactions.
2
. Results and Discussion
Cu-TDPAT catalyst was prepared by a solvothermal method according to the reported
procedure [76]. The SEM image of Cu-TDPAT sample clearly showed that most of the MOF particles
presented polyhedral shapes (Figure S1). The crystal size of the Cu-TDPAT sample was in the range
of 10–40 µm. The powder XRD pattern of the as-synthesized Cu-TDPAT (Figure 1) matched well with
the published results [76], confirming the formation of the intended crystalline framework. Nitrogen
physisorption measurements demonstrated the porosity and stability of Cu-TDPAT after removing
2
the included and coordinated solvents (Figure S2, Table S1). Its BET surface area was 1855 m /g.
˝
Thermogravimetric data showed that Cu-TDPAT was stable up to a temperature of 250 C (Figure S4).
Figure 1. X-ray diffraction patterns for Cu-TDPAT samples, as-synthesized (red); and used after five
catalysis cycles (black).
2
.1. Cu-TDPAT as a Solid Catalyst for the N-Arylation of 5-Methyl-2-(1H)-Pyridone
To test the use of Cu-TDPAT as a catalytic copper complex, iodobenzene and 5-methyl-2-(1H)-
pyridone were selected as coupling partners in the initial screening of optimal reaction conditions
Scheme 1) as the coupling product of these two substrates, 5-methyl-1-phenyl-2-(1H)-pyridone, also
(
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Molecules 2015, 20, 21178–21192
known as pirfenidone (1), has been a widely used drug for the treatment of idiopathic pulmonary
fibrosis (IPF) [77,78].
3
H C
H
3
C
I
5
% catalyst
solvent
N
O
+
O
+
N
H
N
O
1
2
Scheme 1. Coupling reaction of iodobenzene and 5-methyl-2-(1H)-pyridone.
The experimental results under various conditions are presented in Table 1. It was found that
˝
no product was observed after 2 h at 80 C (Table 1, entry 2), indicating that the coupling reaction
proceeded with difficulty at or below this temperature. With increasing temperature, the yields of
pirfenidone (1) increased gradually (Table 1, compare entries 3, 4, 5). The highest yield of 1 was
˝
˝
obtained at 140 C. A further temperature increase to 160 C only gave 1 in 14% yield after 2 h due
to the decomposition of the MOF (Figure S5), revealing that the combined effects of temperature and
reaction media, such as base and solvent molecules, reduced the stability of the MOF. Considering
˝
the stability of Cu-TDPAT, all the subsequent experiments were conducted at 120 C. In the absence
of Cu-TDPAT, no product was obtained (Table 1, entry 1), illustrating that Cu-TDPAT promoted the
N-arylation reaction.
Table 1. Goldberg-type C–N coupling reaction of iodobenzene and 5-methyl-2-(1H)-pyridone over
a
copper MOFs and copper salts .
˝
Entry
Catalyst
Solvent
Base
K CO
T ( C)
1 (%)
2 (%)
1
2
3
4
5
6
7
8
9
DMSO
DMSO
DMSO
DMSO
DMSO
120
80
n.r
n.r
9
n.r
n.r
1
2
3
3
3
3
3
3
3
3
3
3
Cu-TDPAT
Cu-TDPAT
Cu-TDPAT
Cu-TDPAT
Cu-TDPAT
Cu-TDPAT
Cu-TDPAT
Cu-TDPAT
Cu-TDPAT
Cu-TDPAT
Cu-TDPAT
Cu-TDPAT
Cu-TDPAT
CuI
K CO
2
K CO
100
120
140
160
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
2
b
b
K CO
63 (90 )
70
3 (4 )
2
K CO
3
1
n.r
n.r
2
n.r
3
3
n.r
4
4
5
4
2
DMSO
K CO
14
2
Toluene
1,2-Dichlorobenzene
DMF
K CO
n.r
n.r
34
n.r
61
57
n.r
49
80
71
38
29
2
K CO
2
K CO
2
10
11
12
13
14
15
16
17
18
19
20
21
1,4-Dioxane
DMSO
K CO
2
KOH
Cs CO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
2
3
Et N
3
NaOMe
K CO
2
3
3
3
3
3
3
3
CuCl
K CO
2
Cu(OAc)2
Cu(NO3)2
CuBTC
K CO
2
K CO
2
5
2
2
2
K CO
88
43
31
2
Cu(NO ) + BTC
DMSO
DMSO
K CO
3
2
2
Cu(NO ) + TDPAT
K CO
2
3
2
a
Reaction conditions: PhI (1 mmol), pyridone (1 mmol), MOFs (0.05 mmol, based on copper), base (2 mmol),
b
solvent (5 mL), 2 h; Data of reaction for 8 h; The symbol n.r represents no reaction.
It has been found that the choice of solvent is crucial to the outcome of C–N coupling
reactions [16,29]. In order to determine the best reaction medium, the coupling reaction was also
conducted in other solvents (Table 1, entries 7–10). DMSO was found to be the best solvent for
the N-arylation of 5-methyl-2-(1H)-pyridone (Table 1, entry 4). Reaction in DMF gave the coupled
product in a low yield. On the other hand, weakly polar solvents, like 1,2-dichlorobenzene and
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Molecules 2015, 20, 21178–21192
1
,4-dioxane, and non-polar solvents, such as toluene, were not suitable for this process, revealing the
dramatic effects of the solvent on the C–N coupling reactions. Recent studies showed that DMSO
acts as an oxidant for metal species in the formation of C–S and C–Se bonds by cross coupling
reactions [79,80], but in our experiments, no dimethyl sulfide, the reduction product of DMSO, was
detected, implying that here DMSO is only acting as an effective polar solvent. The effects of bases
on the C–N coupling reaction was also investigated. Among the bases tested potassium carbonate,
cesium carbonate, potassium hydroxide and sodium methoxide were effective for the formation of
the desired product and gave similar results (Table 1, compare entries 4, 11, 12 and 14). On the other
hand, triethylamine (Table 1, entry 13) did not effectively improve the N-arylation reaction, contrary
to previously reported results [79]. One possibility is that the interaction of substrate molecules with
catalyst was impeded due to the coordination of triethylamine with the copper ion on the MOF.
˝
According to the above results, we conducted the C–N coupling reactions in DMSO at 120 C
for 8 h in the presence of K CO as the standard reaction conditions. The coupling reaction afforded
2
3
1
as the main product in 90% yield and the by-product 2 in 4% yield, respectively (Figure 2, Table 1,
entry 4). The existence of small amount of 2 reflected the fact that 5-methyl-2-(1H)-pyridone has an
accessible tautomer, 5-methyl-2-hydroxypyridine, in the reaction system [81].
2
.2. Heterogeneity of the Reaction
To verify whether the catalysis of Cu-TAPAT is truly heterogeneous or, on the contrary, is
due to some leached copper species present in the reaction solutions, we performed a hot-filtration
experiment: the Cu-TAPAT solid catalyst was removed from a hot solution by filtration one hour after
initiating the catalytic test. The filtrate was further reacted for another 7 h. No significant catalytic
conversion was observed (Figure 2), indicating that the reaction was terminated upon removal of the
catalyst. On the other hand, inductively coupled plasma atomic emission spectroscopy (ICP-AES)
analysis of the filtrate showed that there was only about 1 ppm of copper in the solution. These
results suggested that the reaction proceeded over the MOF surface in a heterogeneous fashion, with
the open copper sites on the axis of paddle-wheel SBUs within the MOF being responsible for the
promotion of the C–N coupling reaction [82].
Figure 2. Yield as a function of reaction time in the coupling reaction of 5-methyl-2-(1H)-pyridone
˝
and iodobenzene with Cu-TDPAT as catalyst at 120 C. ˝: catalyst removed from the suspension after
h. Reaction conditions: PhI (1 mmol), pyridone (1 mmol), Cu-TDPAT (0.05 mmol, based on copper),
K CO (2 mmol), DMSO (5 mL).
1
2
3
2
.3. Comparison with Other Homogeneous Copper Catalysts
For comparison, several copper salts, CuI, CuCl, Cu(OAc)2 and Cu(NO ) , were used as
3 2
homogeneous catalysts for the same reaction (Table 1, entries 15–18). The experimental results
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Molecules 2015, 20, 21178–21192
showed that both copper(I) salts—CuI and CuCl—produced pirfenidone in high yield, while the
copper(II) salts resulted in relative low yields of coupled product. A widely used MOF, namely
CuBTC [83] (Figures S6 and S7) that was constructed from paddle-wheel type copper clusters and
1
,3,5-benzenetricarboxylate molecules, also exhibited high activity in the C–N coupling reaction
between iodobenzene and 5-methyl-2-(1H)-pyridone (Table 1, entry 19), but the poor stability of
CuBTC under the reaction conditions prevented its recycling. Similar phenomena were reported
by Garcia [75] and Kantam [84]. In the case of CuBTC, a high yield (88%) of 1 was obtained, which
was much higher than that of the homogeneous catalytic processes catalyzed by Cu(NO ) or both
3
2
Cu(NO ) and BTC (Table 1, entries 18 and 20). Moreover, the same result was also observed in the
3
2
comparison of Cu-TDPAT and Cu(NO ) /TDPAT (Table 1, entries 4 and 21). Owing to the same
3
2
amount of copper species being used in the heterogeneous and homogeneous reaction systems, the
above results further reveal that the high density of open copper sites within the MOF were the active
sites of the MOF catalyst and responsible for the enhanced C–N coupling reaction rates.
2
.4. Reusability of the Cu-TDPAT Catalyst
A marked advantage of heterogeneous catalysis is the possibility of recovering and reusing
the catalysts after the reaction. The recycle of the Cu-TDPAT catalyst was further examined in
the coupling reaction of 5-methyl-2-(1H)-pyridone with iodobenzene (Figure 3). Pirfenidone was
obtained in 85%, 83%, 85%, 81% and 81% yields in successive 4 h cycles. The results demonstrated
that Cu-TDPAT exhibited good reusability in the Goldberg-type C–N coupling reaction. The image
(Figure S1b) and XRD patterns (Figure 1) of the Cu-TDPAT catalyst after five reaction runs indicated
that the particle shape, the crystallinity and the chemical structure of Cu-TDPAT were almost
completely maintained. The presence of a little bit of powder can be attributed to the degradation
of a few crystal particles induced by the stirring and the effect of the reaction medium. The nitrogen
physisorption measurements further demonstrated the porosity and stability of Cu-TDPAT after use
(Figure S3). The changes in surface area and pore volume of the used Cu-TDPAT (Table S1) are
probably due to the adsorption of a few reactant or product molecules in the MOF cavities [85,86].
This hypothesis was supported by the changes of thermogravimetric data, in which more weight loss
(about 2%) was observed for the used Cu-TDPAT sample (Figure S4).
Figure 3. Reuse of Cu-TDPAT in the Goldberg-type C–N coupling reaction of iodobenzene
and 5-methyl-2-(1H)-pyridone. Reaction condition: PhI (1 mmol), pyridone (1 mmol), Cu-TDPAT
˝
0.05 mmol, based on copper), K CO (2 mmol), DMSO (5 mL), 4 h, temperature 120 C.
2 3
(
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Molecules 2015, 20, 21178–21192
2
.5. Generality of the N-Arylation Reaction
The generality of the C–N coupling reaction was investigated under the standard reaction
conditions. Initially various halobenzenes were subjected to the reaction conditions. It was found that
bromobenzene provided the corresponding N-arylated pyridone (Table 2, entry 1) and N-arylated
pyrrolidone (Table 2, entry 2) derivatives in moderate yield, while chlorobenzene was unreactive
under these conditions (Table 2, entry 3). Then, the N-arylation reactions of other primary and
secondary amines with iodobenzene were examined (Table 2, entries 4–12). The results showed that a
wide range of amines, including aliphatic amines, aryl amines and N–H heterocycles, could undergo
the C–N coupling reactions smoothly to afford the expected N-arylation products in moderate yields.
Table 2. Ullmann and Goldberg type C–N coupling reactions of halobenzenes with various amines
and amides over Cu-TDPAT *.
Entry
(R R )NH
ArX
Yield (%)
1
2
Br
1
39 (2 a)
Br
Cl
I
2
3
4
5
6
7
37
n.r
51
54
43
35
I
I
I
CH3
NH2
I
I
HO
8
9
59
O
55
I
I
I
10
11
12
56
72 (93 b)
61 (91 b)
N
H
*
Reaction conditions: halobenzenes (1 mmol), amine derivatives (1 mmol), MOFs (0.05 mmol, based on
copper), K2CO3 (2 mmol), DMSO (5 mL), 2 h, temperature 120 C. The yield of 2; b Data of reaction for
˝
a
8
h. The symbol of n.r represents no reaction.
In the case of indole, the coupling product, 1-phenylindole, can be obtained in 93% yield after
h, which is comparable to the homogeneous system results [28,79], indicating the high activity
8
of Cu-TDPAT. N-Methylaniline derivatives bearing electron-withdrawing and electron-donating
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Molecules 2015, 20, 21178–21192
groups on the benzene ring afforded obviously different results under the standard reaction
conditions. When 4-methoxy-N-methylaniline was subjected to the reaction, a good yield (54%)
of the desired product was obtained thanks to the electron-donating effect of the methoxy
group. However the coupling reactions of 4-nitro-N-methylaniline proceeded with difficulty to
give the N-arylation product in a low yield (Table 2, entry 7). These results demonstrated
that the electronic properties of the substituent(s) on the aryl amine play an important role in
determining its reactivity in the C–N coupling reactions. Compared to 4-methoxy-N-methylaniline,
the reaction of 2-methoxy-N-methylaniline gave a relative low yield of the expected product due
to the steric hindrance of the adjacent methoxy group (Table 2, entry 6). Secondary amides are
a particularly challenging substrate class for cross couplings due to the large size of secondary
amides and their relatively low nucleophilicity (compared to amines) [87,88]. The reaction of
N-methylbenzamide (Table 2, entry 10) with iodobenzene afforded a 56% yield of the tertiary amide,
N-methyl-N-phenylbenzamide, within 2 h in the N-arylation reaction, implying that Cu-TDPAT
showed a higher activity than copper(I) thiophenecarboxylate (CuTC) [88] in the N-arylation reaction
of secondary amides.
Table 3 provides a comparison of the results obtained for the Cu-TDPAT catalytic system with
other reported heterogeneous catalytic systems in the cross-coupling reaction of imidazole with
iodobenzene, further indicating the higher activity of this Cu(II) coordination polymer compared
to the other reported systems. Considering the chemical structure and rht-topology of Cu-TDPAT, its
high catalytic activity can be attributed to the high density of open copper sites within Cu-TDPAT
framework and the high pore volume and large open windows that may reduce the diffusional
limitation of the substrate and product [85].
Table 3. Comparison of activity of different heterogeneous catalysts in the N-arylation reaction of
imidazole and iodobenzene.
Catalyst *
Reaction Conditions
Yield
Reference
˝
CuI/Meso-N-C-1
CuI/PSP
DMSO, KOH, 125 C, 24 h
88%
65%
91%
23%–92%
91%
[42]
[48]
[52]
˝
H O, K PO , 120 C, 8 h
H O, KOH, 120 C, 12 h
Toluene, Cs CO , 100 C, 8 h
DMSO, K CO , 120 C, 8 h
2
3
4
˝
Cu-MPTA-1
Cu/SiO2
Cu-TDPAT
2
˝
[44]
2
3
˝
This study
2
3
*
Meso-N-C-1, PSP, MPTA-1 and SiO2 represent mesoporous nitrogen doped carbon, polystyrene-supported
pyrrole-2-carbohydrazide, mesoporous polytriallylamine, and amine or imine-modified silica, respectively.
2
.6. Mechanistic Considerations
Although the mechanism of Ullmann and Goldberg type C–N coupling reactions in the
presence of copper compounds has been widely studied, and four mechanistic pathways involving
oxidative addition/reductive elimination, single electron transfer (SET), σ-bond metathesis and
π-complexation, respectively, have been proposed [89,90], copper-mediated C–N coupling reactions
are still in some sense unpredictable. In order to investigate the function of Cu-TDPAT in the
coupling reaction, X-band (9.06 GHz) electron paramagnetic resonance (EPR) spectra of the reaction
˝
system were recorded at 90 C. The EPR spectra of the reaction mixture were dominated by
2+
2+
a broad signal at g = 2.107 (Figure S8), which could be attributed to Cu –Cu dimers or
mononuclear Cu2 ions [91,92], indicating that the copper atoms on the MOF catalyst exist mainly
as Cu(II) species in the reaction mixtures. Compared to the spectra of pure Cu-TDPAT (Figure S9),
the decrease of the intensity of EPR signal of the reaction mixture with time and the change
of g-value indicated the occurrence of interaction between reaction substrates (iodobenzene and
+
5
-methyl-2-(1H)-pyridone) and copper sites. No any organic radical species was detected, revealing
that the SET mechanism could be discounted. This was further supported by the experiment in
which no effect on the turnover frequency of the coupling reaction was observed when the free
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Molecules 2015, 20, 21178–21192
radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was added to the reaction system.
Moreover, the σ-bond metathesis pathway and oxidative addition/reductive elimination pathway
could also be eliminated due to the difficulty in forming the corresponding intermediates, because the
halobenzene molecules and amine species bonding to the same copper ion from axis might dissociate
the MOF, rendering it non-recyclable. Therefore a possible mechanism for the N-arylation is that the
halobenzene molecule interacts with copper ion first and forms a π-complex, then the amine species
attacks the halobenzene activated by copper, giving the coupling product.
3
. Experimental Section
3
.1. General Information
All solvents and chemicals were obtained commercially and were used as received without
further purification. Cu-TDPAT [76] and CuBTC [83] were synthesized according to the reported
procedures, respectively. The catalysts samples were activated as follows: the as-synthesized MOF
sample was soaked in dry methanol for 12 h, separated from the mixture, and then the process was
repeated four times to remove the high boiling point solvates used in preparations.
Powder X-ray diffraction was performed on a D8 Advance instrument (Bruker, Karlsruhe,
Germany) using Cu–Kα radiation (λ = 1.5406 Å) at room temperature with a scan speed of 0.5 s
˝
1
13
per step and a step size of 0.02 . H-NMR and C-NMR data were collected on Bruker ARX-400
or Bruker ARX-600 spectrometers (Bruker) at 400 MHz and 101 or 151 MHz, respectively, using
CDCl or DMSO-d solutions with tetramethylsilane as an internal standard. Molecular weights
3
6
were obtained on an Aglilent 6410 Triple Quad LC-MS mass spectrometer (Agilent Technologies,
Palo Alto, CA, USA). Scanning electron microscope (SEM) images were obtained on Hitachi S 4300
(Hitachi, Tokyo, Japan) and JEOL-2010 (JEOL, Tokyo, Japan) instruments at room temperature.
Inductively coupled plasma atomic emission spectroscopy (ICP-AES) analysis was performed on
an IRIS Intrepid ER/S instrument (Thermo Elemental, Waltham, MA, USA). Nitrogen sorption
˝
measurement was performed at ´196 C on a ASAP 2020 (Micromeritics, Norcross, GA, USA).
˝
A sample of approximately 50 mg was outgassed at 150 C for 12 h and then nitrogen isotherm
˝
at ´196 C was measured in liquid nitrogen bath using UHP-grade (99.999%) gas source. The
Brunauer-Emmett-Teller (BET) surface area of Cu-TDPAT and CuBTC was calculated based on the
nitrogen absorption isotherm. Thermogravimetric analysis (TGA) was performed on a TG 209F3
instrument (Netzsch, Selb, Germany) under nitrogen atmosphere (250 mL/min). The sample was
˝
˝
˝
heated at a constant rate of 10 C/min from 40 C to 400 C. The continuous wave (CW) EPR spectra
of the reaction mixture in toluene at X-Band were measured using a JES-FA200 spectrometer (JEOL),
microwave frequency 9.06 GHz, power of the microwave 0.998 mW) at 90 C. The data for pure
˝
Cu-TDPAT were obtained from powder samples at room temperature.
3
.2. Catalytic Reactions
The coupling reaction was performed as follows: in a typical process, 5-methyl-2-(1H)-pyridone
(1 mmol), aryl halide (1 mmol), base (2 mmol) and solvent (5 mL) were added to an oven-dried
tube containing 5% (based on copper) MOF catalyst or copper salt. The mixture was stirred at
desired temperature for 2 h. After being cooled to room temperature, the catalyst was filtrated and
washed with ethyl acetate. The products were isolated by a series 1500 preparative high performance
liquid chromatography system (SSI, Charlotte, NC, USA) equipped with a UV-VIS detector, using a
Kromasil C18 column (50 ˆ 250 mm) and gradient elution with a H O (A)-acetonitrile (B) the mobile
2
phase. The gradient program was 0 min, 10% B; 20 min, 35% B. The flow rate of mobile phase was
4
0 mL/min, and the detection wavelength was 220 nm. Fractions were collected and evaporated to
afford the pure products.
1
5
-Methyl-1-phenyl-2-(1H)-pyridone. H-NMR (400 MHz; CDCl ): δ 7.41 (t, J = 7.0 Hz, 2H), 7.36
3
(t, J = 7.7 Hz, 1H), 7.32 (d, J = 7.8 Hz, 2H), 7.21 (d, J = 9.2 Hz, 1H), 7.07 (s, 1H), 6.53 (d, J = 9.2 Hz, 1H),
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Molecules 2015, 20, 21178–21192
2
1
.04 (s, 3H); 13C-NMR (151 MHz; DMSO-d ): δ 160.95, 143.52, 141.47, 136.49, 129.46, 128.42, 127.17,
6
+
20.67, 114.60, 16.77; MS (ESI) m/z: 186.23 ([M + H] ; Calcd for C H NO + H 186.09, found: 186.23).
12
11
1
5
-Methyl-2-phenoxypyridine.
H-NMR (400 MHz, DMSO-d ): δ 7.98 (d, J = 1.7 Hz, 1H), 7.66
6
(
dd, J = 8.3 Hz, 2.3 Hz, 1H), 7.39 (t, J = 7.9 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1H), 7.07 (d, J = 7.8 Hz, 2H),
13
6
1
1
.92 (d, J = 8.3 Hz, 1H), 2.23 (s, 3H). C-NMR (151 MHz; DMSO-d ): δ 161.63, 154.89, 147.41, 141.16,
6
+
30.08, 128.52, 124.57, 121.15, 111.62, 17.38. MS (ESI) m/z: 186.23 ([M + H] ; Calcd for C H NO + H
12
11
86.09, found: 186.23).
1
N-Methyldiphenylamine. H-NMR (400 MHz, CDCl ): δ 7.40 (t, J = 7.9Hz, 4H), 7.15 (d, J = 8.2 Hz, 4H),
3
13
7
4
.08 (t, J = 7.3 Hz, 2H), 3.43 (s, 3H). C-NMR (151 MHz; DMSO-d ): δ 149.09, 129.62, 121.57, 120.57,
0.01. MS (ESI) m/z: 184.11 ([M + H] ; Calcd for C H N + H 184.11, found: 184.11).
6
+
13
13
1
N-Methyl-N-(4-methoxy)phenylaniline. H-NMR (400 MHz, CDCl ): δ 7.24–7.17 (m, 2H), 7.17–7.12
(
3
13
m, 2H), 7.00 (m, 1H), 6.84–6.77 (m, 2H), 6.69–6.64 (m, 2H), 3.88 (s, 3H), 3.31 (s, 3H). C-NMR (151
MHz; DMSO-d ): δ 156.36, 149.92, 142.13, 129.30, 126.35, 118.55, 115.89, 115.27, 55.65, 40.63. MS (ESI)
6
+
m/z: 214.09 ([M + H] ; Calcd for C H NO + H 214.12, found: 214.09).
14
15
N-Methyl-N-(2-methoxy)phenylaniline. 1H-NMR (400 MHz, DMSO-d ): δ 7.33–7.22 (m, 1H), 7.17 (dd,
6
J = 12.3 Hz, 3 Hz, 1H), 7.13 (d, J = 6.1 Hz, 1H), 7.11 (t, J = 7.9 Hz, 2H), 6.99 (t, J = 7.5 Hz, 1H), 6.62 (t,
J = 7.2 Hz, 1H), 6.51 (d, J = 8.2 Hz, 2H), 3.71 (s, 3H), 3.13 (s, 3H). 13C-NMR (151 MHz; DMSO-d ): δ
6
1
2
52.13, 148.33, 142.22, 129.12, 123.74, 122.84, 121.88, 119.22, 119.13, 113.32, 56.79, 37.87. MS (ESI) m/z:
+
14.09 ([M + H] ; Calcd for C H NO + H 214.12, found: 214.09).
14
15
1
N-Methyl-N-(4-nitro)phenylaniline. H-NMR (400 MHz, DMSO-d ): δ 8.05 (d, J = 6.2 Hz, 2H), 7.50 (t,
6
J = 7.8 Hz, 2H), 7.35 (t, J = 7.5 Hz, 1H), 7.31 (d, J = 6.7 Hz, 2H), 6.74 (d, J = 6.3 Hz, 2H), 3.38 (s, 3H).
1
3
C-NMR (151 MHz; DMSO-d ): δ 154.13, 146.44, 137.58, 130.67, 127.16, 126.96, 126.10, 113.02, 40.85.
6
+
MS (ESI) m/z: 229.11 ([M + H] ; Calcd for C H N O + H 229.10, found: 229.11).
13
12
2
2
1
2
-(Phenylamino)propanoic acid. H-NMR (400 MHz, DMSO-d ): δ 7.06 (t, J = 7.8 Hz, 2H), 6.55
6
13
(
(
(
d, J = 8 Hz, 2H), 6.55–6.54 (m, 1H), 3.92 (q, J = 7.0 Hz, 1H), 1.36 (d, J = 7.0 Hz, 3H). C-NMR
101 MHz; DMSO-d ): δ 177.62, 147.78, 128.83, 116.25, 112.46, 51.32, 18.21. MS (ESI) m/z: 166.09
[M + H] ; Calcd for C H NO + H 166.09, found: 166.09).
6
+
9
11
2
1
Methyl 2-(phenylamino)propanoate. H-NMR (400 MHz, DMSO-d ): δ 7.07 (t, J = 7.8 Hz, 2H), 6.58–6.56
(
6
13
m, 1H), 6.53 (d, J = 7.7 Hz, 2H), 4.05 (q, J = 7.0 Hz, 1H), 3.62 (s, 3H), 1.37 (d, J = 7.0 Hz, 3H). C-NMR
(
1
151 MHz, DMSO-d ): δ 174.96, 147.57, 128.90, 116.45, 112.30, 50.90, 50.70, 18.12 (s, 1H). MS (ESI) m/z:
6
+
80.11 ([M + H] ; Calcd for C H NO + H 180.10, found: 180.11).
10
13
2
1
N-Phenyl-2-pyrrolidone. H-NMR (400 MHz, DMSO-d ): δ 7.65 (d, J = 7.8 Hz, 2H), 7.37 (t, J = 8.0 Hz,
6
2
H), 7.12 (t, J = 7.4 Hz, 1H), 3.83 (t, J = 7.0 Hz, 2H), 2.48 (t, J = 8.4 Hz, 2H), 2.06 (m, J = 7.5 Hz, 2H).
13
C-NMR (151 MHz; DMSO-d ): δ 174.28, 140.07, 129.06, 124.26, 119.80, 48.50, 32.78, 17.86. MS (ESI)
6
+
m/z: 162.09 ([M + H] ; Calcd for C H NO + H 162.09, found: 162.09).
10
11
1
N-Methyl-N-benzoylaniline. H-NMR (400 MHz, CDCl ): δ 7.30 (t, J = 7.2 Hz, 2H), 7.21 (t, J = 7.4 Hz,
3
2
(
H), 7.18 (t, J = 4.5 Hz, 1H), 7.14 (d, J = 8.1 Hz, 2H), 7.11 (t, J = 6.4 Hz, 1H), 7.02 (d, J = 7.5 Hz, 2H), 3.48
s, 3H). 13C-NMR (151 MHz; DMSO-d ): δ 170.01, 145.02, 136.77, 129.82, 129.53, 128.64, 128.19, 127.50,
6
+
1
26.88, 38.34. MS (ESI) m/z: 212.11 ([M + H] ; Calcd for C H NO + H 212.11, found: 212.11).
14
13
N-Phenylindole. 1H-NMR (400 MHz, DMSO-d ): δ 7.68 (d, J = 7.6 Hz, 1H), 7.64 (d, J = 3.3 Hz, 1H),
6
13
7
.59–7.54 (m, 5H), 7.45–7.35 (m, 1H), 7.09–7.24 (m, 2H), 6.75 (d, 1H). C-NMR (151 MHz; DMSO-d6):
δ 139.63, 135.62, 130.26, 129.65, 128.84, 126.82, 124.24, 122.80, 121.48, 120.76, 110.82, 104.06. MS (ESI)
+
m/z: 194.11 ([M + H] ; Calcd for C H N + H 194.10, found: 194.11).
14
11
21186

Molecules 2015, 20, 21178–21192
1
N-Phenylimidazole. H-NMR (400 MHz, DMSO-d ): δ 8.32 (br, 1H), 7.79 (br, 1H), 7.66 (d, J = 7.6 Hz,
6
13
2
1
1
H), 7.52 (t, J = 7.8 Hz, 2H), 7.43–7.29 (m, 1H), 7.17 (br, 1H). C-NMR (101 MHz; DMSO-d ): δ 136.94,
35.60, 129.93, 129.84, 126.92, 120.40, 118.30. MS (ESI) m/z: 145.08 ([M + H] ; Calcd for C H N + H
45.08, found: 145.08).
6
+
9
8
2
3
.3. Reuse of Cu-TDPAT
The aforementioned procedure was used with 5-methyl-2-(1H)-pyridone (1 mmol), iodobenzene
1 mmol), K CO (2 mmol), DMSO (5 mL) and 5% Cu-TDPAT (based on copper). The reaction mixture
was magnetically stirred at 120 C for 4 h. The liquid solution was removed, and the solid mixture
was washed with ethyl acetate (5 mL). The resulting solid phase was reused for further reactions
without previous purification.
(
2
3
˝
4
. Conclusions
In summary, a detailed investigation of N-arylation reaction of 5-methyl-2-(1H)-pyridone with
halobenzenes was carried out using Cu-TDPAT, a metal-organic framework with high density of open
copper sites within its framework, as an efficient heterogeneous catalyst. It has been demonstrated
that Cu-TDPAT can improve the N-arylation reaction of a wide variety of amines and amides with
iodobenzene or bromobenzene efficiently. The experimental results prove that Cu-TDPAT is stable
to the conditions of Ullmann and Goldberg type coupling reactions, and the open copper sites on
the axis of paddle-wheel SBUs within MOF are responsible for the promotion of the C–N coupling
reaction. Further work is in progress to broaden the scope of this catalytic system to other substrates
and to better understand the reaction mechanism.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com /1420-3049/
2
0/12/19756/s1.
Acknowledgments: The work was supported by the national natural science foundation of China (Grant No.
1346005, 21307168 and 21277009).
2
Author Contributions: All authors contributed to the appearance of this article. W.Q. and H.H. conceived and
designed the experiments; W.L. performed experiments and collated data. C.G. carried out the synthesis of the
Cu-TDPAT. C.L., L.S., G.B. and G.Z. analyzed the data. W.Q. and W.L. wrote the paper.
Conflicts of Interest: The authors declare no conflict of interest.
References
1
.
Bikker, J.A.; Brooijmans, N.; Wissner, A.; Mansour, T.S. Kinase domain mutations in cancer: Implications
for small molecule drug design strategies. J. Med. Chem. 2009, 52, 1493–1509. [CrossRef] [PubMed]
Balle, T.; Perregaard, J.; Ramirez, M.T.; Larsen, A.K.; Soby, K.K.; Liljefors, T.; Andersen, K. Synthesis
and structure-affinity relationship investigations of 5-heteroaryl-substituted analogues of the antipsychotic
sertindole. A new class of highly selective α1 adrenoceptor antagonists. J. Med. Chem. 2003, 46, 265–283.
2
.
[
CrossRef] [PubMed]
Popowycz, F.; Routier, S.; Joseph, B.; Merour, J.Y. Synthesis and reactivity of 7-azaindole
1H-pyrrolo[2,3-b]pyridine). Tetrahedron 2007, 63, 1031–1064. [CrossRef]
Surry, D.S.; Buchwald, S.L. Diamine ligands in copper-catalyzed reactions. Chem. Sci. 2010, 1, 13–31.
CrossRef] [PubMed]
3.
4.
5.
6.
7.
(
[
Monnier, F.; Taillefer, M. Catalytic C–C, C–N, and C–O Ullmann-type coupling reactions. Angew. Chem.
Int. Ed. 2009, 48, 6954–6971. [CrossRef] [PubMed]
Ma, D.W.; Cai, Q. Copper/amino acid catalyzed cross-couplings of aryl and vinyl halides with
nucleophiles. Acc. Chem. Res. 2008, 41, 1450–1460. [CrossRef] [PubMed]
Casitas, A.; Ribas, X. The role of organometallic copper(III) complexes in homogeneous catalysis. Chem. Sci.
2
013, 4, 2301–2318. [CrossRef]
21187

Molecules 2015, 20, 21178–21192
8
.
Klapars, A.; Antilla, J.C.; Huang, X.H.; Buchwald, S.L. A general and efficient copper catalyst for the
amidation of aryl halides and the N-arylation of nitrogen heterocycles. J. Am. Chem. Soc. 2001, 123,
7
727–7729. [CrossRef] [PubMed]
9
1
1
.
Taillefer, M.; Cristau, H.J.; Cellier, P.; Spindler, J.F. Method for Forming a Carbon-Carbon or
Carbon-Heteroatom Linkage. WO Patent 053,885-A, 20 December 2002.
0. Klapars, A.; Huang, X.; Buchwald, S.L. A general and efficient copper catalyst for the amidation of aryl
halides. J. Am. Chem. Soc. 2002, 124, 7421–7428. [CrossRef] [PubMed]
1. Audisio, D.; Messaoudi, S.; Peyrat, J.B.; Brion, J.D.; Alami, M. A general copper powder-catalyzed
Ullmann-type reaction of 3-halo-4(1H)-quinolones with various nitrogen-containing nucleophiles.
J. Org. Chem. 2011, 76, 4995–5005. [CrossRef] [PubMed]
1
2. Zhou, F.T.; Guo, J.J.; Liu, J.G.; Ding, K.; Yu, S.Y.; Cai, Q. Copper-catalyzed desymmetric intramolecular
Ullmann C–N coupling: An enantioselective preparation of indulines. J. Am. Chem. Soc. 2012, 134,
1
4326–14329. [CrossRef] [PubMed]
3. Antila, J.C.; Klapars, A.; Buchwald, S.L. The copper-catalyzed N-arylation of indoles. J. Am. Chem. Soc.
002, 124, 11684–11688. [CrossRef]
4. Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. Accelerating effect induced by the structure of R-amino acid in
the copper-catalyzed coupling reaction of aryl halides with R-amino acids. Synthesis of benzolactam-V8.
J. Am. Chem. Soc. 1998, 120, 12459–12467. [CrossRef]
1
1
2
1
5. Kim, J.; Chang, S. Ammonium salts as an inexpensive and convenient nitrogen source in the Cu-catalyzed
amination of aryl halides at room temperature. Chem. Commun. 2008, 26, 3052–3054. [CrossRef] [PubMed]
6. Hammoud, H.; Schmitt, M.; Bihel, F.; Antheaume, C.; Bourguignon, J.J. Direct guanidinylation of aryl and
heteroarylhalides via copper-catalyzed cross-coupling reaction. J. Org. Chem. 2012, 77, 417–423. [CrossRef]
1
[
PubMed]
7. Lu, Z.; Twieg, R.J.; Huang, S.D. Copper-catalyzed amination of aromatic halides with
-N,N-dimethylaminoethanol as solvent. Tetrahedron Lett. 2003, 44, 6289–6292. [CrossRef]
8. Lu, Z.; Twieg, R.J. A mild and practical copper catalyzed amination of halothiophenes. Tetrahedron 2005, 61,
03–918. [CrossRef]
9. Kwong, F.Y.; Klapars, A.; Buchwald, S.L. Copper-catalyzed coupling of alkylamines and aryl iodides:
An efficient system even in an air atmosphere. Org. Lett. 2002, 4, 581–584. [CrossRef] [PubMed]
0. Wang, N.; Chen, B.; Ma, S.M. Studies on electrophilic cyclization of N-(buta-2,3-dienyl)amides with
N-bromosuccinimide and its applications. Adv. Synth. Catal. 2014, 356, 485–492. [CrossRef]
1. Tye, J.W.; Weng, Z.; Johns, A.M.; Incarvito, C.D.; Hartwig, J.F. Copper complexes of anionic nitrogen ligands
in the amidation and imidation of aryl halides. J. Am. Chem. Soc. 2008, 130, 9971–9983. [CrossRef] [PubMed]
2. Goodbrand, H.B.; Hu, N.X. Ligand-accelerated catalysis of the Ullmann condensation: Application to hole
conducting triarylamines. J. Org. Chem. 1999, 64, 670–674. [CrossRef]
3. Gujadhur, R.K.; Bates, C.G.; Venkataraman, D. Formation of aryl-nitrogen, aryl-oxygen, and aryl-carbon
bonds using well-defined copper(I)-based catalysts. Org. Lett. 2001, 3, 4315–4317. [CrossRef] [PubMed]
4. Yang, K.; Qiu, Y.T.; Li, Z.; Wang, Z.Y.; Jiang, S. Ligands for copper-catalyzed C–N bond forming reactions
with 1 mol % CuBr as Catalyst. J. Org. Chem. 2011, 76, 3151–3159. [CrossRef] [PubMed]
5. Shafir, A.; Buchwald, S.L. Highly selective room-temperature copper-catalyzed C–N coupling reactions.
J. Am. Chem. Soc. 2006, 128, 8742–8743. [CrossRef] [PubMed]
6. Shafir, A.; Lichtor, P.A.; Buchwald, S.L. N-versus O-arylation of aminoalcohols: Orthogonal selectivity in
copper-based catalysts. J. Am. Chem. Soc. 2007, 129, 3490–3491. [CrossRef] [PubMed]
7. Xia, N.; Taillefer, M. A very simple copper-catalyzed synthesis of anilines by employing aqueous ammonia.
Angew. Chem. Int. Ed. 2009, 48, 337–339. [CrossRef] [PubMed]
8. Chen, H.; Lei, M.; Hu, L.H. Synthesis of 1-aryl indoles via coupling reaction of indoles and aryl halides
catalyzed by CuI/metformin. Tetrahedron 2014, 70, 5626–5631. [CrossRef]
9. Ghorbani-Vaghei, R.; Hemmati, S.; Veisi, H. An in situ generated CuI/metformin complex as a novel and
efficient catalyst for C–N and C–O cross-coupling reactions. Tetrahedron Lett. 2013, 54, 7095–7099. [CrossRef]
0. Yang, S.L.; Wu, C.Q.; Ruan, M.B.; Yang, Y.Q.; Zhao, Y.X.; Niu, J.J.; Yang, W.; Xu, J.W. Metal- and ligand-free
Ullmann-type C–O and C–N coupling reactions promoted by potassium tert-butoxide. Tetrahedron Lett.
1
1
1
2
2
2
2
2
2
2
2
2
2
3
2
9
2
012, 53, 4288–4292. [CrossRef]
21188

Molecules 2015, 20, 21178–21192
3
1. Yuan, Y.; Thome, I.; Kim, S.H.; Chen, D.; Beyer, A.; Bonnamour, J.; Zuidema, E.; Chang, S.; Bolm, C.
Dimethyl sulfoxide/potassium hydroxide: A superbase for the transition metal-free preparation of
cross-coupling products. Adv. Synth. Catal. 2010, 352, 2892–2898. [CrossRef]
3
3
3
2. Cano, R.; Ramon, D.J.; Yus, M. Transition-metal-free O-, S-, and N-arylation of alcohols, thiols, amides,
amines, and related heterocycles. J. Org. Chem. 2011, 76, 654–660. [CrossRef] [PubMed]
3. Creutz, S.E.; Lotito, K.J.; Fu, G.C.; Peters, J.C. Photoinduced Ullmann C–N coupling: Demonstrating the
viability of a radical pathway. Science 2012, 338, 647–651. [CrossRef] [PubMed]
4. Ziegler, D.T.; Choi, J.; Munoz-Molina, J.M.; Bissember, A.C.; Peters, J.C.; Fu, G.C. A versatile approach
to Ullmann C–N couplings at room temperature: New families of nucleophiles and electrophiles for
photoinduced, copper-catalyzed processes. J. Am. Chem. Soc. 2013, 135, 13107–13112. [CrossRef] [PubMed]
5. Majek, M.; von Jacobi Wangelin, A. Ambient-light-mediated copper-catalyzed C–C and C–N bond
formation. Angew. Chem. Int. Ed. 2013, 52, 5919–5921. [CrossRef] [PubMed]
6. Strieter, E.R.; Bhayana, B.; Buchwald, S.L. Mechanistic studies on the copper-catalyzed N-arylation of
amides. J. Am. Chem. Soc. 2009, 131, 78–88. [CrossRef] [PubMed]
7. Yu, H.Z.; Jiang, Y.Y.; Fu, Y.; Liu, L. Alternative mechanistic explanation for ligand-dependent selectivities
in copper-catalyzed N- and O-arylation reactions. J. Am. Chem. Soc. 2010, 132, 18078–18091. [CrossRef]
3
3
3
[PubMed]
3
3
4
4
8. Jones, G.O.; Liu, P.; Houk, K.N.; Buchwald, S.L. Computational explorations of mechanisms and
ligand-directed selectivities of copper-catalyzed Ullmann-type reactions. J. Am. Chem. Soc. 2010, 132,
6
205–6213. [CrossRef] [PubMed]
9. Satish, G.; Reddy, K.H.V.; Ramesh, K.; Kumar, B.S.P.A.; Nageswar, Y.V.D. An elegant protocol for the
synthesis of N-substituted pyrroles through C–N cross coupling/aromatization process using CuFe O4
2
nanoparticles as catalyst under ligand-free conditions. Tetrahedron Lett. 2014, 55, 2596–2599. [CrossRef]
0. Costa, M.V.; Viana, G.M.; de Souza, T.M.; Malta, L.F.B.; Aguiar, L.C.S. Copper-catalyzed C–N cross-coupling
reactions for the preparation of aryl diamines applying mild conditions. Tetrahedron Lett. 2013, 54,
2
332–2335. [CrossRef]
1. Reddy, K.H.V.; Satish, G.; Ramesh, K.; Karnakar, K.; Nageswar, Y.V.D. An efficient synthesis of
N–substituted indoles from indoline/indoline carboxylic acid via aromatization followed by C–N
cross-coupling reaction by using nano copper oxide as a recyclable catalyst. Tetrahedron Lett. 2012, 53,
3
061–3065. [CrossRef]
4
2. Zhang, P.F.; Yuan, J.Y.; Li, H.R.; Liu, X.F.; Xu, X.; Antonietti, M.; Wang, Y. Mesoporous nitrogen-doped
carbon for copper mediated Ullmann-type C–O/–N/–S cross-coupling reactions. RSC Adv. 2013, 3,
1
890–1895. [CrossRef]
4
3. Xiao, R.; Zhao, H.; Cai, M. MCM-41-immobilized bidentate nitrogen copper(I) complex: A highly efficient
and recyclable catalyst for Buchwald N-arylation of indoles. Tetrahedron 2013, 69, 5444–5450. [CrossRef]
4. Likhar, P.R.; Roy, S.; Roy, M.; Kantam, M.L.; De, R.L. Silica immobilized copper complexes: Efficient and
reusable catalysts for N-arylation of N(H)-heterocycles and benzyl amines with aryl halides and arylboronic
acids. J. Mol. Catal. A: Chem. 2007, 271, 57–62. [CrossRef]
4
4
4
4
5. Choudary, B.M.; Sridhar, C.; Kantam, M.L.; Venkanna, G.T.; Sreedhar, B. Design and evolution of copper
apatite catalysts for N-arylation of heterocycles with chloro- and fluoroarenes. J. Am. Chem. Soc. 2005, 127,
9
948–9949. [CrossRef] [PubMed]
6. Chouhan, G.; Wang, D.; Alper, H. Magnetic nanoparticle-supported proline as a recyclable and recoverable
ligand for the CuI catalyzed arylation of nitrogen nucleophiles. Chem. Commun. 2007, 45, 4809–4811.
[
CrossRef] [PubMed]
7. Mostafalu, R.; Kaboudin, B.; Kazemi, F.; Yokomatsu, T. N-arylation of amines: C–N coupling of amines with
arylboronic acids using Fe O magnetic nanoparticles-supported EDTA-Cu(II) complex in water. RSC Adv.
3
4
2
014, 4, 49273–49279. [CrossRef]
4
8. Huang, L.; Yu, R.; Zhu, X.; Wan, Y. A recyclable Cu-catalyzed C–N coupling reaction in water and its
application to synthesis of imidazo[1,2-a]quinoxaline. Tetrahedron 2013, 69, 8974–8977. [CrossRef]
9. Huang, Y.B.; Yang, C.T.; Yi, J.; Deng, X.J.; Fu, Y.; Liu, L. Cu-catalyzed carbon-heteroatom coupling reactions
under mild conditions promoted by resin-bound organic ionic bases. J. Org. Chem. 2011, 76, 800–810.
4
[CrossRef] [PubMed]
21189

Molecules 2015, 20, 21178–21192
5
5
5
0. Islam, S.M.; Mondal, S.; Mondal, P.; Roy, A.S.; Tuhina, K.; Salam, N.; Mobarak, M. A reusable polymer
supported copper catalyst for the C–N and C–O bond cross-coupling reaction of aryl halides as well as
arylboronic acids. J. Org. Chem. 2012, 696, 4264–4274. [CrossRef]
1. Yang, B.; Mao, Z.X.; Zhu, X.H.; Wan, Y.Q. Functionalised chitosan as a green, recyclable, supported catalyst
for the copper-catalysed Ullmann C–N coupling reaction in water. Catal. Commun. 2015, 60, 92–95.
[CrossRef]
2. Salam, N.; Kundu, S.K.; Roy, A.S.; Mondal, P.; Roy, S.; Bhaumik, A.; Islam, S.M. Cu-grafted mesoporous
organic polymer: A new recyclable nanocatalyst for multi-component, N-arylation and S-arylation
reactions. Catal. Sci. Technol. 2013, 3, 3303–3316.
5
3. Corma, A.; Garcia, H.; Llabres, I.; Xamena, F.X. Engineering metal organic frameworks for heterogeneous
catalysis. Chem. Rev. 2010, 110, 4606–4655. [CrossRef] [PubMed]
5
4. Chughtai, A.H.; Ahmad, N.; Younus, H.A.; Laypkov, A.; Verpoort, F. Metal-organic frameworks: Versatile
heterogeneous catalysts for efficient catalytic organic transformations. Chem. Soc. Rev. 2015, 44, 6804–6849.
[CrossRef] [PubMed]
5
5. Dhakshinamoorthy, A.; Opanasenko, M.; Cejka, J.; Garcia, H. Metal organic frameworks as heterogeneous
catalysts for the production of fine chemicals. Catal. Sci. Technol. 2013, 3, 2509–2540. [CrossRef]
5
6. Gomez-Lor, B.; Gutierrez-Puebla, E.; Iglesias, M.; Monge, M.A.; Ruiz-Valero, C.; Snejko, N.
In (OH) (BDC) (BDC = 1,4-Benzendicarboxylate): An In(III) supramolecular 3D framework with
1.5
2
3
catalytic activity. Inorg. Chem. 2002, 41, 2429–2432. [CrossRef] [PubMed]
5
7. Llabresi Xamena, F.X.; Abad, A.; Corma, A.; Garcia, H. MOFs as catalysts: Activity, reusability and
shape-selectivity of a Pd-containing MOF. J. Catal. 2007, 250, 294–298. [CrossRef]
5
8. Dhakshinamoorthy, A.; Alvaro, M.; Chevreau, H.; Horcajada, P.; Devic, T.; Serre, C.; Garcia, H. Iron(III)
metal-organic frameworks as solid Lewis acids for the isomerization of α-pinene oxide. Catal. Sci. Technol.
2
012, 2, 324–330. [CrossRef]
5
6
6
9. Gu, J.M.; Kim, W.S.; Huh, S. Size-dependent catalysis by DABCO-functionalized Zn-MOF with
one-dimensional channels. Dalton Trans. 2011, 40, 10826–10829. [CrossRef] [PubMed]
0. Dang, D.; Wu, P.; He, C.; Xie, Z.; Duan, C. Homochiral metal-organic frameworks for heterogeneous
asymmetric catalysis. J. Am. Chem. Soc. 2010, 132, 14321–14323. [CrossRef] [PubMed]
1. Llabres i Xamena, F.X.; Casanova, O.; Tailleur, R.G.; Garcia, H.; Corma, A. Metal organic frameworks
(
MOFs) as catalysts: A combination of Cu2+ and Co2+ MOFs as an efficient catalyst for tetralin oxidation.
J. Catal. 2008, 255, 220–227. [CrossRef]
6
6
6
2. Dhakshinamoorthy, A.; Alvaro, M.; Garcia, H. Aerobic oxidation of benzylic alcohols catalyzed by
metal-organic frameworks assisted by TEMPO. ACS Catal. 2011, 1, 48–53. [CrossRef]
3. Marx, S.; Kleist, W.; Baiker, A. Synthesis, structural properties, and catalytic behavior of Cu-BTC and
mixed-linker Cu-BTC-PyDC in the oxidation of benzene derivatives. J. Catal. 2011, 281, 76–87. [CrossRef]
4. Fei, H.H.; Shin, J.; Meng, Y.S.; Adelhardt, M.; Sutter, J.; Meyer, K.; Cohen, S.M. Reusable oxidation catalysis
using metal-monocatecholato species in a robust metal-organic framework. J. Am. Chem. Soc. 2014, 136,
4
965–4973. [CrossRef] [PubMed]
6
6
6
6
6
5. Maksimchuk, N.V.; Kovalenko, K.A.; Fedin, V.P.; Kholdeeva, O.A. Cyclohexane selective oxidation over
metal-organic frameworks of MIL-101 family: Superior catalytic activity and selectivity. Chem. Commun.
2
012, 48, 6812–6814. [CrossRef] [PubMed]
6. Laurier, K.G.M.; Vermoortele, F.; Ameloot, R.; de Vos, D.E.; Hofkens, J.; Roeffaers, M.B.J. Iron(III)-based
metal-organic frameworks as visible light photocatalysts. J. Am. Chem. Soc. 2013, 135, 14488–14491.
[CrossRef] [PubMed]
7. Wang, D.K.; Huang, R.K.; Liu, W.J.; Sun, D.R.; Li, Z.H. Fe-based MOFs for photocatalytic CO reduction:
2
Role of coordination unsaturated sites and dual excitation pathways. ACS Catal. 2014, 4, 4254–4260.
[CrossRef]
8. Deng, M.; Ling, Y.; Xia, B.; Chen, Z.; Zhou, Y.; Liu, X.; Yue, B.; He, H. Synthesis of isoreticular
zinc(II)-phosphonocarboxylate frameworks and their application in the Friedel-Crafts benzylation reaction.
Chem. Eur. J. 2011, 17, 10323–10328. [CrossRef] [PubMed]
9. Phan, N.T.S.; Le, K.K.A.; Phan, T.D. MOF-5 as an efficient heterogeneous catalyst for Friedel-Crafts
alkylation reactions. Appl. Catal. A Gen. 2010, 382, 246–253. [CrossRef]
21190

Molecules 2015, 20, 21178–21192
7
0. Ravon, U.; Savonnet, M.; Aguado, S.; Domine, M.E.; Janneau, E.; Farrusseng, D. Engineering of
coordination polymers for shape selective alkylation of large aromatics and the role of defects.
Microporous Mesoporous Mater. 2010, 129, 319–329. [CrossRef]
7
1. Dhakshinamoorthy, A.; Opanasenko, M.; Cejka, J.; Garcia, H. Metal organic frameworks as solid catalysts
in condensation reactions of carbonyl groups. Adv. Synth. Catal. 2013, 355, 247–268. [CrossRef]
2. Phan, N.T.S.; Nguyen, T.T.; Nguyen, C.V.; Nguyen, T.T. Ullmann-type coupling reaction using
metal-organic framework MOF-199 as an efficient recyclable solid catalyst. Appl. Catal. A: Gen. 2013,
7
4
57, 69–77. [CrossRef]
7
3. Wang, M.; Yuan, B.Z.; Ma, T.M.; Jiang, H.F.; Li, Y.W. Ligand-free coupling of phenols and alcohols with aryl
halides by arecyclable heterogeneous copper catalyst. RSC Adv. 2012, 2, 5528–5530. [CrossRef]
7
4. Dang, T.T.; Zhu, Y.H.; Ghosh, S.C.; Chen, A.Q.; Chai, C.L.L.; Seayad, A.M. Atmospheric pressure
aminocarbonylation of aryl iodides using palladium nanoparticles supported on MOF-5. Chem. Commun.
2
012, 48, 1805–1807. [CrossRef]
7
7
5. Dhakshinamoorthy, A.; Alvaro, M.; Concepcion, P.; Garcia, H. Chemical instability of Cu (BTC) by
reaction with thiols. Catal. Commun. 2011, 12, 1018–1021. [CrossRef]
6. Li, B.Y.; Zhang, Z.J.; Li, Y.; Yao, K.X.; Zhu, Y.H.; Deng, Z.Y.; Yang, F.; Zhou, X.J.; Li, G.H.; Wu, H.H.; et al.
3
2
Enhanced binding affinity, remarkable selectivity, and high capacity of CO by dual functionalization of a
2
rht-type metal-organic framework. Angew. Chem. Int. Ed. 2012, 51, 1412–1415. [CrossRef] [PubMed]
7. Gant, T.G.; Sarshar, S. New Substituted N-Arylpyridone Derivatives Useful for Treating e.g., Idiopathic
Pulmonary Fibrosis, Cirrhosis, Diffuse Parenchymal Lung Disease, Mediastinal Fibrosis, Tuberculosis, and
Rheumatoid Arthritis. U.S. Patent 0,319,026 A1, 20 June 2008.
7
78. Okazaki, A.; Ohkura, N.; Fujimura, M.; Katayama, N.; Kasahara, K. Effects of pirfenidone on increased
cough reflex sensitivity in guinea pigs. Pulm. Pharmacol. Ther. 2013, 26, 603–608. [CrossRef] [PubMed]
79. Yadav, D.K.T.; Rajak, S.S.; Bhanage, B.M. N-arylation of indoles with aryl halides using copper/glycerolas
a mild and highly efficient recyclable catalytic system. Tetrahedron Lett. 2014, 55, 931–935. [CrossRef]
80. Ricordi, V.G.; Freitas, C.S.; Perin, G.; Lenardao, E.J.; Jacob, R.G.; Savegnago, L.; Alves, D. Glycerol as
a recyclable solvent for copper-catalyzed cross-coupling reactionsof diaryldiselenides with aryl boronic
acids. Green Chem. 2012, 14, 1030–1034. [CrossRef]
8
1. Frank, J.; Katritzky, A.R. Tautornericpyridines. Part XV. Pyridone-hydroxypyridine equilibriain solvents of
differing polarity. J. Chem. Soc. Perkin Trans. 1976, 2, 1428–1431. [CrossRef]
8
2. Alaerts, L.; Seguin, E.; Poelman, H.; Thibault-Starzyk, F.; Jacobs, P.A.; de Vos, D.E. Probing the Lewis acidity
and catalytic activity of the metal-organic framework [Cu (btc) ] (BTC = Benzene-1,3,5-tricarboxylate).
3
2
Chem. Eur. J. 2006, 12, 7353–7363. [CrossRef] [PubMed]
3. Schlichte, K.; Kratzke, T.; Kaskel, S. Improved synthesis, thermal stability and catalytic properties of the
metal-organic framework compound Cu (BTC) . Microporous Mesoporous Mater. 2004, 73, 81–88. [CrossRef]
4. Priyadarshini, S.; Amal Joseph, P.J.; Lakshmi Kantam, M.; Sreedhar, B. Copper MOF: Scope and limitation
in catalytic hydroxylation and nitration of aryl halides. Tetrahedron 2013, 69, 6409–6414. [CrossRef]
5. Wee, L.H.; Bajpe, S.R.; Janssens, N.; Hermans, I.; Houthoofd, K.; Kirschhock, C.E. A.; Martens, J.A.
8
8
8
3
2
Convenient synthesis of Cu (BTC) encapsulated Keggin heteropolyacid nanomaterial for application in
3
2
catalysis. Chem. Commun. 2010, 46, 8186–8188. [CrossRef] [PubMed]
8
6. Li, C.Q.; Qiu, W.G.; Long, W.; Deng, F.; Bai, G.M.; Zhang, G.Z.; Zi, X.H.; He, H. Synthesis of
porphyrin@MOFs type catalysts through “one-pot” self-assembly. J. Mol. Catal. A Chem. 2014, 393, 166–170.
[
CrossRef]
7. Yin, J.; Buchwald, S.L. Palladium-catalyzed intermolecular coupling of aryl halides and amides. Org. Lett.
000, 2, 1101–1104. [CrossRef] [PubMed]
8. Quan, Z.J.; Xia, H.D.; Zhang, Z.; Da, Y.X.; Wang, X.C. An efficient copper-catalyzed N-arylation of amides:
Synthesis of N-arylacrylamides and 4-amido-N-phenylbenzamides. Tetrahedron 2013, 69, 8368–8374.
8
8
2
[CrossRef]
8
9
9. Sperotto, E.; Klink, G.P. M.V.; Koten, G.V.; Vries, J.G. D. The mechanism of the modified Ullmann reaction.
Dalton Trans. 2010, 39, 10338–10351. [CrossRef] [PubMed]
0. Sambiagio, C.; Marsden, S.P.; John Blacker, A.; McGowan, P.C. Copper catalyzed Ullmann type chemistry:
From mechanistic aspects to modern development. Chem. Soc. Rev. 2014, 43, 3525–3550. [CrossRef]
[PubMed]
21191

Molecules 2015, 20, 21178–21192
9
1. Mkami, H.E.L.; Mohideen, M.I.H.; Pal, C.; McKinlay, A.; Scheimann, O.; Morris, R.E. EPR and magnetic
studies of a novel copper metal organic framework (STAM-I). Chem. Phys. Lett. 2012, 544, 17–21. [CrossRef]
2. Simenas, M.; Kobalz, M.; Mendt, M.; Eckold, P.; Krautscheid, H.; Banys, J.; Poppl, A. Synthesis, structure,
and electron paramagnetic resonance study of a mixed valent metal-organic framework containing Cu2
paddle-wheel units. J. Phys. Chem. C 2015, 119, 4898–4907. [CrossRef]
9
Sample Availability: Sample of the compound Cu-TDPAT is available from the authors.
©
2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open
access article distributed under the terms and conditions of the Creative Commons by
Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
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