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Direct CN coupling of azoles with ethers via

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framework catalysis

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DOI: 10.1016/j.jiec.2016.08.025

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 Journal of Industrial and Engineering Chemistry 44 (2016) 136145

Contents lists available at ScienceDirect

Journal of Industrial and Engineering Chemistry

journal homepage: www.elsevier.com/locate/jiec

Direct CN coupling of azoles with ethers via oxidative CH activation

under metalorganic framework catalysis
Khoa D. Nguyen, Son H. Doan, Anh N.V. Ngo, Tung T. Nguyen, Nam T.S. Phan*
Department of Chemical Engineering, HCMC University of Technology, VNU-HCM, 268 Ly Thuong Kiet, District 10, Ho Chi Minh City, Viet Nam

A R T I C L E I N F O A B S T R A C T

Article history:
Received 2 July 2016 A metalorganic framework Fe3O(BPDC)3 was synthesized, and used as a productive heterogeneous
Received in revised form 23 August 2016 catalyst for the direct CN coupling of azoles with ethers via oxidative CH activation to produce azole
Accepted 24 August 2016 derivatives. The MOF-based catalyst displayed higher catalytic efciency than many homogeneous
Available online 31 August 2016 catalysts as well as several MOFs in the transformation. The MOF-based catalyst could be reused many
times for the synthesis of azole derivatives by the direct CN coupling of azoles with ethers without a
Keywords: noteworthy deterioration in catalytic efciency. To the best of our knowledge, this direct CN coupling
Azoles reaction was not previously performed in the presence of heterogeneous catalysts.
Coupling
2016 The Korean Society of Industrial and Engineering Chemistry. Published by Elsevier B.V. All rights
CH activation
reserved.
Fe3O(BPDC)3
Ethers

Introduction published the rst example of a FeCl3-catalyzed oxidative CN

Azole derivatives have attracted signicant attention as
valuable skeletons in numerous nitrogen-containing biologically
active natural products, agrochemicals, pharmaceutical candi-
dates, and functional materials [17]. N-Alkylation of azoles using
alkyl halides in the presence of a strong base has been among the
most popular approaches to achieve functional azoles [8]. Over
the past decade, transition metal-catalyzed cross-coupling
reactions have emerged as a powerful protocol for the construc-
tion of carboncarbon and carbonheteroatom bonds, offering
greener methods for the synthesis of these heterocycles [913].
However, the preinstallation of reactive functional groups should
be a major anxiety from atom-economical and environmental
aspects [1416]. The coupling via direct CH activation would
provide shorter and more productive synthetic schemes to
prepare azole derivatives [14,17]. Xia et al. previously reported
a FeCl2-catalyzed direct C

N bond formation between imidazoles
and benzylic hydrocarbons via oxidative activation of C

H bonds
[8]. Xia and Chen demonstrated a FeCl2-catalyzed oxidative
coupling reaction of C

H bonds adjacent to a nitrogen atom in
amides and sulfonamides with the N

H bond in azoles [18].
Saidulu et al. also synthesized N-alkyl and N-benzyl azoles via
iron-catalyzed oxidative C

H bond functionalization adjacent to
nitrogen atom in amides and anilines [19]. Pan et al. previously
* Corresponding author. Fax: +84 8 38637504.
E-mail address: ptsnam@hcmut.edu.vn (N.T.S. Phan).
coupling reactions of azoles with ethers to produce azole
derivatives via direct CH activation [20]. To accomplish a more
environmentally advantageous protocol for the synthesis of
functional azoles, the transformation should be conducted using
heterogeneous catalysts.
Potential applications of metalorganic frameworks (MOFs) in
many domains have been comprehensively investigated during the
last decade, concentrating on gas storage, gas separation, energy
technologies, sensors, optics, drug storage and delivery, heavy
metal ion extraction, and catalysis [2125]. A series of diverse
MOFs could be produced by connecting abundant metal cations of
miscellaneous oxidation states and coordination geometries with
various organic joining ligands, thus offering several benets as
compared to ordinary porous crystalline materials [26,27]. The
utilization of MOFs as heterogeneous catalysts has lately acquired
considerable curiosity from both academics and industry, and
related reports have expanded dramatically in the last few years
[2832]. Either the metal joining points or the organic linkers in
the framework, being arranged in predictable and tunable style as a
consequence of the nature of MOFs, could catalyze organic
reactions [31,33,34]. Indeed, a plenty number of transformations
have been performed using MOF-based catalysts [3539]. Iron-
based metalorganic frameworks were previously synthesized and
employed as catalysts for organic reactions, directing on oxidation
or related reactions [4043]. In this work, we wish to describe the
direct CN coupling of azoles with ethers via oxidative CH
activation to produce azole derivatives utilizing the metalorganic
framework Fe3O(BPDC)3 as a productive heterogeneous catalyst. To

http://dx.doi.org/10.1016/j.jiec.2016.08.025
1226-086X/ 2016 The Korean Society of Industrial and Engineering Chemistry. Published by Elsevier B.V. All rights reserved.
 K.D. Nguyen et al. / Journal of Industrial and Engineering Chemistry 44 (2016) 136145
the best of our knowledge, this direct CN coupling reaction was
not previously performed in the presence of heterogeneous
catalysts.
Experimental
Synthesis of the metalorganic framework Fe3O(BPDC)3
The catalyst was synthesized in compliance with a marginally
modied literature method [44]. In a standard preparation, a
mixture of acetic acid (CH3COOH; 0.4 mL, 7 mmol) and H2BPDC
(H2BPDC = biphenyl-4,40 -dicarboxylic acid; 0.08 g, 0.33 mmol) was
added to DMF (DMF = N,N0 -dimethylformamide; 30 mL).
FeCl36H2O (0.1667 g, 0.62 mmol) was dissolved in DMF (10 mL),
and the resulting solution was then added dropwise to the solution
of acetic acid and H2BPDC. The mixture was magnetically stirred
for 1 h to accomplish a transparent solution. This solution was then
delivered in four 20-mL vials. The vials were heated at 120  C in an
oven for 48 h. After this period, the vials were cooled down to room
temperature, and the crystals were isolated by decantation. The Fe-
MOF was washed with DMF (3  10 mL), and immersed in
dichloromethane (3  10 mL) at room temperature. The product
was then dried at 140  C for 6 h under vacuum in a Shlenkline,
providing 0.0762 g of the Fe3O(BPDC)3 in the form of light orange
crystals (76% based on biphenyl-4,40 -dicarboxylic acid).
Catalytic studies
In a representative experiment, a mixture of benzimidazole
(0.118 g, 1 mmol), and diphenyl ether (0.1 mL) as an internal
standard in dichloroethane (4 mL) was added into a 25 mL round
bottom ask containing the Fe3O(BPDC)3 catalyst (0.015 g, 5 mol%).
The catalyst concentration was calculated in relation to the iron/
benzimidazole molar ratio. The reaction mixture was magnetically
stirred for 3 min to disperse the Fe-MOF catalyst in the reaction
solution. Isochroman (0.50 mL, 4 mmol) and di-tert-butyl peroxide
(0.62 mL, 3 mmol) were then added. The resulting mixture was
magnetically stirred at 80  C for 120 min. Reaction yield was
recorded by withdrawing samples from the reaction mixture at
different time periods, quenching with KOH solution (5%, 1 mL).
The organic constituents were then extracted into ethyl acetate
(2 mL), dried over anhydrous Na2SO4, analyzed by GC concerning
diphenylether. The major product, 1-(isochroman-1-yl)-1H-benzo
[d]imidazole, was puried by column chromatography on silica gel
(ethyl acetate/hexane = 1:1). The product specication was addi-
tionally authenticated by GCMS, 1H NMR, and 13C NMR. To inspect
the recyclability of the catalyst, after the rst run, the Fe-MOF was
collected by centrifugation, washed many times with dichloro-
methane, activated in a Shlenkline under vacuum at 140  C for 3 h,
and reused for the next run.
Results and discussion
Catalyst synthesis and characterization
The Fe3O(BPDC)3 was synthesized in a yield of 76% from the
reaction of iron(III) chloride hexahydrate and biphenyl-4,40 -
dicarboxylic acid in DMF by a solvothermal method, in compliance
with a marginally modied literature procedure [44]. A critical
feature in the synthesis of porous MOFs would be the solvent
exchange, as this step would facilitate the removal of pre-
coordinating solvent and pore-lling guest molecules [2125].
During this procedure, the intensively interacting guest formamide
solvent molecules in the as-synthesized iron-based framework
were replaced by dichloromethane that would be easily removed
under vacuum. The framework was characterized by a number of
137
different techniques (Figs. S1S7). A highly sharp peak with 2u of
6.4 was recorded on the XRD diffractogram, revealing that a
crystalline framework was generated (Fig. S1). The SEM micro-
graph indicated that well-shaped crystals with particles sizes of
less than 10 mm were obtained (Fig. S2). The TEM micrograph
displayed that the framework possessed a porous structure,
though its pore structure was complex (Fig. S3). The Fe-MOF
exhibited an average pore diameter of approximately 6.5
(Fig. S4), a value that is still in the microporous regime (<20
diameter pore size). Langmuir surface areas of up to 1800 m2/g
were recorded for the material (Fig. S5), being considerably higher
than those of conventional microporous and mesoporous inorgan-
ic materials. TGA result indicated that the framework was stable up
to over 350  C (Fig. S6). FT-IR spectra of the Fe-MOF displayed a
notable difference as compared to that of the organic linker
(Fig. S7).
Catalytic studies
Effect of temperature
The Fe-MOF was evaluated for its catalytic activity in the direct
CN coupling reaction of benzimidazole with isochroman via
oxidative CH activation to produce 1-(isochroman-1-yl)-1H-
benzo[d]imidazole as the major product (Scheme 1). Beginning
studies focused on the inuence of temperature on the yield of 1-
(isochroman-1-yl)-1H-benzo[d]imidazole. The reaction was car-
ried out at 5 mol% catalyst in dichloroethane for 120 min, using
4 equivalents of isochroman and 3 equivalents of di-tert-butyl
peroxide as the oxidant, at room temperature, 50  C, 60  C, 70  C,
and 80  C, respectively. It was observed that almost no reaction
occurred at room temperature, with less than 1% yield of 1-
(isochroman-1-yl)-1H-benzo[d]imidazole being detected after
120 min. As expected, raising the reaction temperature led to
aconsiderable enhancement in the reaction yield. The transfor-
mation carried out at 60  C afforded 29% yield of 1-(isochroman-
1-yl)-1H-benzo[d]imidazole after 120 min. Performing the direct
CN coupling reaction at 70  C resulted in 70% yield after 120 min.
This value could be amended to 90% when the reaction
temperature was increased to 80  C (Fig. 1). Indeed, in the rst
example of the FeCl3-catalyzed oxidative CN coupling reactions
of azoles with ethers to produce azole derivatives via direct CH
activation, Pan et al. also performed the transformation at 80  C
[20].
Effect of catalyst concentration and reactant molar ratio
Another item that should be explored for the coupling of
benzimidazole with isochroman to produce 1-(isochroman-1-yl)-
1H-benzo[d]imidazole is the catalyst concentration. The reaction
was carried out at 80  C in dichloroethane for 120 min, using
4 equivalents of isochroman and 3 equivalents of di-tert-butyl
peroxide as the oxidant, in the presence of 1 mol%, 3 mol%, 5 mol%,
and 7 mol% catalyst, respectively. It should be mentioned that 5%
yield of 1-(isochroman-1-yl)-1H-benzo[d]imidazole was detected
after 120 min in the absence of the solid catalyst, conrming the
necessity of the Fe-MOF for the transformation. The coupling
O
H
N O Fe3O(BPDC)3 N
+
N di-tert-butyl peroxide N
dichloroethane
Scheme 1. The direct CN coupling of benzimidazole with isochroman via
oxidative CH activation using Fe3O(BPDC)3 catalyst.
138 K.D. Nguyen et al. / Journal of Industrial and Engineering Chemistry 44 (2016) 136145

100 100

80 80

Yield (%)
Yield (%)

60 60

40 40

20 20

0 0
RT 50 60 70 80 1:1 1:2 1:3 1:4
Temperature (oC) Reactant molar ratio

Fig. 1. Yields of 1-(isochroman-1-yl)-1H-benzo[d]imidazole at varied temperature. Fig. 3. Yields of 1-(isochroman-1-yl)-1H-benzo[d]imidazole at varied benzimid-
azole:isochroman molar ratios.

reaction could afford 61% yield after 120 min in the presence of
1 mol% Fe-MOF catalyst. Using 3 mol% catalyst, the yield of
1-(isochroman-1-yl)-1H-benzo[d]imidazole could be upgraded
to 78% after 120 min. Raising the catalyst concentration to 5 mol
% led to a pronounced enhancement in the formation of
1-(isochroman-1-yl)-1H-benzo[d]imidazole, with 90% yield being
achieved after 120 min. Using more than 5 mol% catalyst was found
to be unnecessary as the reaction yield was not improved
signicantly (Fig. 2). The impact of the reactant molar ratio should
also be taken into accounts. The reaction was then carried out in
dichloroethane at 80  C for 120 min, in the presence of 5 mol%
catalyst, using 3 equivalents of di-tert-butyl peroxide as the
oxidant, using 1, 2, 3, and 4 equivalents of isochroman, respectively.
It was found that the reaction using 1 equivalent of isochroman
progressed with difculty, affording only 13% yield of 1-(isochro-
man-1-yl)-1H-benzo[d]imidazole after 120 min. Raising the
amount of isochroman facilitated the transformation, providing
90% yield of 1-(isochroman-1-yl)-1H-benzo[d]imidazole after
120 min for the reaction using 4 equivalents of isochroman (Fig. 3).
Effect of oxidant and oxidant concentration
With regard to other coupling reactions via the direct activation
of CH bonds, the utilization of an oxidant would be important
forthe coupling of benzimidazole with isochroman to produce 1-
(isochroman-1-yl)-1H-benzo[d]imidazole using the MOF-based
catalyst. It was therefore determined to explore the impact of
different oxidants on the formation of 1-(isochroman-1-yl)-1H-
benzo[d]imidazole, having employed di-tert-butyl peroxide, tert-
butyl hydroperoxide in water, tert-butyl hydroperoxide in decane,
cumyl hydroperoxide, hydrogen peroxide, AgNO3, and K2S2O8 as
the oxidant for the transformation, respectively. The direct CN
coupling reaction was then carried out in dichloroethane at 80  C
for 120 min, in the presence of 5 mol% catalyst, using 4 equivalents
of isochroman and 3 equivalents of the oxidant. It should be
mentioned that only 8% yield of 1-(isochroman-1-yl)-1H-benzo[d]
imidazole was detected after 120 min in the absence of the
oxidant, supporting the requirement of using the oxidant for the
coupling reaction between benzimidazole and isochroman.
Hydrogen peroxide, AgNO3, and K2S2O8 were found to be
unsuitable for the transformation, affording 33%, 24%, and 19%
yields, respectively, after 120 min. The reaction using tert-butyl
hydroperoxide as the oxidant could proceed to 55% yield after
120 min, while 77% yield was observed for that using tert-butyl
hydroperoxide in decane. Among these oxidants, di-tert-butyl
peroxide expressed the best exhibition with 90% yield of
100

80

100
60
Yield (%)

80
40
Yield (%)

60
20

40
0
e
3

t
2
8

ne

P
2O

an
id
O

20
TB 2O
O

TB
ca

ox
N
S2

id
TB P/H
H
Ag

D
ox
de

er
K2

op
P/

no
H

dr

0
hy
yl

0 1 3 5
um
C

Catalyst concentration (mol%)

Oxidant
Fig. 2. Yields of 1-(isochroman-1-yl)-1H-benzo[d]imidazole at varied catalyst
concentrations. Fig. 4. Yields of 1-(isochroman-1-yl)-1H-benzo[d]imidazole with varied oxidants.
 K.D. Nguyen et al. / Journal of Industrial and Engineering Chemistry 44 (2016) 136145 139

100 100

80 80
Yield (%)

60 60

Yield (%)
40 40

20
20

0
0
0 1 2 3 4

To e

e
ne

Te cet O
te

oe n

e
e
n- ene

hy itril
n
Oxidant concentration (eqv.)

an
ra
yc tan

S
ta
le

xa

ic rofu
ce

th
lu

tra on
Xy

ep

he

D
la
H

d
lo
Fig. 5. Yields of 1-(isochroman-1-yl)-1H-benzo[d]imidazole at varied oxidant

or
hy

hl
Et
C
concentrations.

D
Solvent

Fig. 6. Yields of 1-(isochroman-1-yl)-1H-benzo[d]imidazole with varied solvents.

1-(isochroman-1-yl)-1H-benzo[d]imidazole being achieved after
120 min (Fig. 4). Moreover, it was noticed that the amount of di-
tert-butyl peroxide also affected the reaction between benzimid-
azole and isochroman. Best result was recorded for the transfor-
mation using 3 equivalents of di-tert-butyl peroxide as the oxidant
(Fig. 5).
Effect of solvent
It was previously reported that the solvent could display an
impressive inuence on the reaction rate of many organic
transformations using solid catalysts. In the rst example of the
FeCl3-catalyzed oxidative CN coupling reactions of azoles with
ethers to produce azole derivatives via direct CH activation, Pan
et al. pointed out that tetrahydrofuran, dichloroethane, and
ethylacetate could be used as solvent for the transformation
[20]. It was therefore determined to study the inuence of different
solvents on the coupling reaction of benzimidazole with isochro-
man to produce 1-(isochroman-1-yl)-1H-benzo[d]imidazole
usingthe Fe-MOF catalyst. The reaction was carried out at
80  C for 120 min, using 4 equivalents of isochroman and
3 equivalents of di-tert-butyl peroxide as the oxidant, in the
presence of 5 mol% catalyst, in p-xylene, toluene, n-heptane,
cyclohexane, ethylacetate, DMSO, acetonitrile, tetrahydrofuran,
dichloroethane, respectively, as solvent. It was noticed that the
Fe3O(BPDC)3-catalyzed coupling reaction of benzimidazole with
isochroman progressed with difculty in p-xylene, n-heptane, and
cyclohexane, with 36%, 33%, and 32% yields being detected after
120 min. Toluene offered better exhibition, affording 49% yield of
1-(isochroman-1-yl)-1H-benzo[d]imidazole after 120 min. Con-
ducting the transformation in ethylacetate, the yield of
1-(isochroman-1-yl)-1H-benzo[d]imidazole could be increased
to 55% after 120 min. The reaction carried out in DMSO could
produce the desired product in a yield of 59% after 120 min, while
cases, the transformation would progress under both heteroge-
neous and homogeneous catalysis conditions as a result of the
leaching problem [45]. In order to probe if active iron species
moved from the solid catalyst were active for the formation of 1-
(isochroman-1-yl)-1H-benzo[d]imidazole in the coupling reac-
tion, a control experiment was conducted. The reaction was then
carried out in dichloroethane at 80  C for 120 min, in the presence
of 5 mol% catalyst, using 4 equivalents of isochroman and
3 equivalents of di-tert-butyl peroxide as the oxidant. After the
rst 20 min reaction time with 26% yield of 1-(isochroman-1-yl)-
1H-benzo[d]imidazole being recorded, the catalyst was removed
from the reaction mixture by centrifugation. The liquid phase was
then shifted to a new ask, and magnetically stirred for an extra
100 min at 80  C with samples being analyzed at different time
periods by GC. It was noticed that almost no further yield of
1-(isochroman-1-yl)-1H-benzo[d]imidazole was observed after
the Fe-MOF catalyst was separated from the reaction mixture
(Fig. 7). These observations would reveal that the coupling
reaction of benzimidazole with isochroman could only progress
in the presence of the solid MOF-based catalyst, and no
100
80
5 mol% catalyst
60
Yield (%)

61% yield was obtained for that carried out in acetonitrile. The
Leaching test
yield of 1-(isochroman-1-yl)-1H-benzo[d]imidazole could be
improved to 83% after 120 min in tetrahydrofuran as solvent. 40
Among these solvents, dichloroethane expressed the best exhibi-
tion, with 90% yield being achieved after 120 min (Fig. 6).
20

Leaching test
0
As the coupling reaction of benzimidazole with isochroman to
0 20 40 60 80 100 120
produce 1-(isochroman-1-yl)-1H-benzo[d]imidazole was per-
formed in liquid phase, the feasibility that some of catalytical- Time (min)
lyactive sites could move into the solution throughout the Fig. 7. Leaching test showed that 1-(isochroman-1-yl)-1H-benzo[d]imidazole
progression of the reaction should be analyzed. In a number of could only be formed in the presence of the solid catalyst.
140 K.D. Nguyen et al. / Journal of Industrial and Engineering Chemistry 44 (2016) 136145

contribution from catalytically active species soluble in the liquid 100

phase was recorded.

Mechanistic studies 80
To receive perception into the pathway of the direct CN
coupling reaction of benzimidazole with isochroman to produce 1- 60

Yield (%)
(isochroman-1-yl)-1H-benzo[d]imidazole, further mechanistic
studies were conducted. In the rst experiment series, the direct
CN coupling reaction was then carried out in dichloroethane at 40
80  C for 120 min, in the presence of 5 mol% catalyst, using
4 equivalents of isochroman and 3 equivalents of di-tert-butyl 20 5 mol% catalyst
peroxide as the oxidant. After the rst 20 min reaction time, Pyridine test
ascorbic acid as the antioxidant was then added to the reaction Pyridine test (activated)

mixture, and the mixture was stirred for an extra 100 min at 80  C 0
with samples being taken at different time periods, and analyzed 0 20 40 60 80 100 120
by GC. It was noticed that the direct CN coupling reaction was Time (min)
immensely affected by the antioxidant. Similarly, the presence of
Fig. 9. Yields of 1-(isochroman-1-yl)-1H-benzo[d]imidazole with catalyst poison.
(2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO) as the antioxidant
in the reaction mixture also led to a drastic deterioration in the
yield of 1-(isochroman-1-yl)-1H-benzo[d]imidazole (Fig. 8). It
could be recommended that the interaction of antioxidant with the for the catalyst deactivation. It should be mentioned that almost no
radicals formed in the reaction mixture would alter the direct CN reaction occurred in the absence of the catalyst but with the
coupling transformation. presence of di-tert-butyl peroxide, and in the absence of di-tert-
In this work, iron sites on the framework were activated by butyl peroxide but with the presence of the catalyst, thus
conventional strategies [2125], combining the solvent exchange underlining the function of both iron sites and the oxidant in
method with thermal treatment under vacuum. Recently, Kim et al. the catalytic cycle.
demonstrated an alternative chemical route for the activation of Based on these notices and the literature [20], the reaction
open metal sites in copper-based MOFs utilizing dichloromethane pathway was proposed, in which isochroman radical was initially
without applying heat [46]. Following this method, the as- formed via the hydrogen abstraction by the di-tert-butyl peroxide
synthesized Fe3O(BPDC)3 was repeatedly soaked in dichloro- in the presence of the MOF-based catalyst. This isochroman radical
methane, and subsequently used as catalyst for the coupling was then converted to the corresponding cation via a single-
reaction without heating under vacuum. It was noted that 90% electron transfer (SET) procedure. Subsequently, a nucleophillic
yield of the expected product was also recorded, conrming the addition of benzimidazole to the cation would form 1-(isochro-
signicance of this chemical activation protocol. In the next man-1-yl)-1H-benzo[d]imidazole and generate the catalyst back
experiment series, control reactions were conducted using to the catalytic cycle (Scheme 2).
pyridine as a catalyst poison. The catalyst was immersed in
pyridine for 24 h at room temperature, and this Fe-MOF sample
was used as catalyst for the direct CN reaction. In another
experiment, the Fe-MOF sample was activated under vacuum
previous to use in the transformation. It was also noticed that the
pyridine immensely affected the catalytic activity of the MOF-
based catalyst in the direct CN coupling reaction (Fig. 9). The fact t
BuOOtBu
that pyridine expressed an enormous impact on the formation of t +
BuOH
O +
1-(isochroman-1-yl)-1H-benzo[d]imidazole would recommend
that the adsorption of pyridine on the Fe-MOF was the reason O
N

N Fe(II)

H t
100 N SET BuOH

N
80

t t
60 BuO-Fe(II) BuO-Fe(III)
Yield (%)

+ +
40 O O

5 mol% catalyst
20
Adding TEMPO
Adding asc orbic acid
0 SET
0 20 40 60 80 100 120
Time (min) Scheme 2. Proposed reaction mechanism of the CN coupling reaction of
benzimidazole with isochroman to produce 1-(isochroman-1-yl)-1H-benzo[d]
Fig. 8. Yields of 1-(isochroman-1-yl)-1H-benzo[d]imidazole with antioxidants. imidazole.
 K.D. Nguyen et al. / Journal of Industrial and Engineering Chemistry 44 (2016) 136145 141

Reaction with different catalysts 100

To resolve the critical aspects of using the Fe-MOF catalyst for
the direct CN coupling reaction of benzimidazole with isochro-
man to produce 1-(isochroman-1-yl)-1H-benzo[d]imidazole, the 80
catalytic activity of the Fe-MOF was compared to that of popular
homogeneous iron catalysts, including Fe(NO3)3, FeCl2, FeBr2,

Yield (%)
60
FeCl3, FeSO4, and Fe2(SO4)3. The direct CN coupling reaction was
then carried out in dichloroethane at 80  C for 120 min, in the
presence of 5 mol% catalyst, using 4 equivalents of isochroman and 40
3 equivalents of di-tert-butyl peroxide as the oxidant. It was
observed that the direct CN coupling reaction using FeBr2 catalyst
20
proceeded with difculty, affording only 16% yield of 1-(isochro-
man-1-yl)-1H-benzo[d]imidazole after 120 min. Similarly, the
FeCl2-catalyzed coupling reaction of benzimidazole with isochro- 0
man produced the desired product in a yield of 20% after 120 min.

)
)

)3
)

)3
)
O

O
O

C
PY
FeCl3 was found to be more active for the direct CN coupling

C
C
C

C
C

PD
D
)(B
AB

AB
B

(B
u(
A
transformation than FeCl2, with 44% yield of 1-(isochroman-1-yl)-

(B
C
(D

)(D
(D

3O
BT

3O
)2

)2

C
1H-benzo[d]imidazole being detected after 120 min. Fe(NO3)3

Fe
i(H
C

BD

Fe
BD

N
(B
displayed lower catalytic activity than FeCl3, and the Fe(NO3)3-

u(
(
o2

C
i2
N
catalyzed direct CN coupling reaction proceeded to 22%

yield after 120 min. FeSO4 and Fe2(SO4)3 should not be used as
catalyst for the direct CN coupling reaction of benzimidazole with
isochroman, as only 12% and 14% yields, respectively, were
observed after 120 min for the transformation. Interestingly,
the solid catalyst exhibited better performance than these
homogeneous iron catalyst, with 90% yield of 1-(isochroman-1-
yl)-1H-benzo[d]imidazole being achieved after 120 min (Fig. 10).
To underline the benets of using this catalyst for the direct C
N coupling reaction of benzimidazole with isochroman to
produce 1-(isochroman-1-yl)-1H-benzo[d]imidazole, the cata-
lytic activity of the Fe3O(BPDC)3 was compared with that of other
MOFs including Ni(HBTC)(BPY), Co2(BDC)2(DABCO), Ni2(BDC)2(-
DABCO), Cu(BDC), Cu2(BDC)2(DABCO), and Fe3O(BDC)3. These
MOFs were synthesized by solvothermal method, and character-
ized according to literature procedures. The reaction was then
carried out in dichloroethane at 80  C for 120 min, in the presence
of 5 mol% catalyst, using 4 equivalents of isochroman and
3 equivalents of di-tert-butyl peroxide as the oxidant. It was
found that the Co2(BDC)2(DABCO)-catalyzed direct CN coupling
reaction of benzimidazole with isochroman via oxidative CH
100
80
60
Yield (%)
C
Catalyst
Fig. 11. Yields of 1-(isochroman-1-yl)-1H-benzo[d]imidazole with different MOFs
as catalysts.
activation progressed with difculty, affording 1-(isochroman-1-
yl)-1H-benzo[d]imidazole in a yield of only 17% after 120 min.
Ni2(BDC)2(DABCO) and Ni(HBTC)(BPY) should not be used as
catalyst for this transformation, with only 19% and 5% yields of the
desired product being detected after 120 min. Cu-MOFs were more
active for the direct CN coupling reaction of benzimidazole with
isochroman than Co-MOFs and Ni-MOFs. The Cu(BDC)-catalyzed
direct CN coupling transformation produced 1-(isochroman-1-
yl)-1H-benzo[d]imidazole in a yield of 62% after 120 min.
Similarly, the reaction using Cu2(BDC)2(DABCO) catalyst offered
65% yield of the desired product after 120 min. Fe3O(BDC)3
exhibited higher catalytic efciency for the transformation than
Cu2(BDC)2(DABCO), with 84% yield of 1-(isochroman-1-yl)-1H-
benzo[d]imidazole being observed after 120 min. Among these
MOFs, Fe3O(BPDC)3 was the catalyst of choice, producing
1-(isochroman-1-yl)-1H-benzo[d]imidazole in 90% yield after
120 min (Fig. 11).
We also tried to obtain isolated yields for the reaction using
different catalysts. The reaction was performed under con-
ditions mentioned earlier. After the experiment, the product
was puried by column chromatography on silica gel. It was
found that 88%, 80%, 61%, 57%, and 39% isolated yields were
achieved the reaction utilizing Fe3O(BPDC)3, Fe3O(BDC)3,
Cu2(BDC)2(DABCO), Cu(BDC), and FeCl3 as catalyst, respectively.

The difference in catalytic performance between two iron-based

MOFs in the reaction could be explained using the feature that
40 Fe3O(BPDC)3 possessed higher surface areas. Certainly, Lang-
muir surface areas of 890 m2/g were recorded for the Fe3O
(BDC)3, while up to 1800 m2/g were achieved for Fe3O(BPDC)3.
20
Xia et al. previously performed the direct CN coupling reaction
of imidazoles with benzylic hydrocarbons, and pointed out that
0 iron salts were more effective as catalyst than copper salts [8].
Pan et al. also published the direct CN coupling reactions of
l2

l3

)3
r2

4
4)
3)

S0
C

C
B

azoles with ethers to produce azole derivatives via direct CH

SO
O
Fe

Fe
Fe

PD
Fe
(N

2(

activation utilizing iron salts as catalyst [20]. Similarly, Xai and

(B
Fe

Fe

3O

Chen revealed that iron salts exhibited higher catalytic

Fe

efciency than other metal salts in the direct CN coupling

Catalyst
reaction between azoles and amides, though no explanation
Fig. 10. Yields of 1-(isochroman-1-yl)-1H-benzo[d]imidazole with different was mentioned [18]. In this work, the reason why Fe-MOFs
homogeneous iron catalysts. offered higher catalytic activity than Cu-MOFs, Co-MOFs, and
142 K.D. Nguyen et al. / Journal of Industrial and Engineering Chemistry 44 (2016) 136145

Ni-MOFs in the transformation still needs further investiga- 1500

tions.

Catalyst recycling studies

As mentioned earlier, the Fe3O(BPDC)3 was noticed to be more
catalytically active than several homogeneous and heterogeneous 1000 (b)

catalysts. One point that should be taken into consideration for the
coupling reaction of benzimidazole with isochroman to produce
1-(isochroman-1-yl)-1H-benzo[d]imidazole is the readiness of
reusability. In the best circumstance, the Fe-MOF catalyst should
be isolated from the reaction mixture without troublesome
experimental handling, and could be reused many times. The
catalyst was therefore explored for reusability in the direct CN
coupling reaction of benzimidazole with isochroman to form
1-(isochroman-1-yl)-1H-benzo[d]imidazole over 6 consecutive
runs. The reaction was then carried out in dichloroethane at
80  C for 120 min, in the presence of 5 mol% catalyst, using
4 equivalents of isochroman and 3 equivalents of di-tert-butyl
peroxide as the oxidant. After 120 min reaction time with 90% yield
of 1-(isochroman-1-yl)-1H-benzo[d]imidazole being observed, the
catalyst was isolated from the reaction mixture by simple
centrifugation, washed with copious amounts of dichloromethane,
dried at 140  C under vacuum in a Shlenkline for 3 h. The recovered
catalyst was then reused in further reaction under duplicate
conditions to those of the rst experiment. It was noticed that the
Fe-MOF catalyst could be recovered and reused many times in the
coupling reaction of benzimidazole with isochroman to form
1-(isochroman-1-yl)-1H-benzo[d]imidazole without a consider-
able deterioration in catalytic activity. Indeed, 88% yield of the
desired product was still recorded in the 6th run (Fig. 12).
Moreover, the structure of the Fe-MOF could be retained during the
course of the transformation, as indicated by XRD (Fig. 13) and
FT-IR (Fig. 14) results of the recovered catalyst.
Reaction of different reactants
The scope of the research was then expanded to the oxidative
CN coupling reactions of different azoles with different ethers to
produce azole derivatives. In the rst experiment series, we
performed the coupling between benzimidazole with several
ethers. The reaction was then carried out in dichloroethane at 80  C
for 120 min, in the presence of 5 mol% catalyst, using 4 equivalents
of isochroman and 3 equivalents of di-tert-butyl peroxide as the
oxidant. The product was puried by column chromatography on
silica gel. Using this procedure, 1-(isochroman-1-yl)-1H-benzo[d]
imidazole was achieved in 88% isolated yield (entry 1). Ethoxy-
ethane was found to exhibit similar reactivity, producing 1-(1-
Lin ( Counts)
500
(a)
0
3 8 13 18 23
2-Theta- Scale
Fig. 13. X-ray powder diffractograms of the fresh (a) and reused (b) catalyst.
ethoxyethyl)-1H-benzo[d]imidazole in 92% yield (entry 2). The
coupling reaction between benzimidazole with 2-ethoxyethyl
acetate progressed with more difcultness, though 75% yield of
2-(1-(1H-benzo[d]imidazol-1-yl)ethoxy)ethyl acetate was still
recorded (entry 3). A more bulky ether, dibenzyl ether, was also
reactive toward the reaction, affording 1-(benzyloxy(phenyl)
methyl)-1H-benzo[d]imidazole in 84% yield (entry 4). Both
tetrahydrofuran and 1,3-dihydroisobenzofuran displayed similar
reactivity as compared to isochroman in the coupling trans-
formation. Indeed, 1-(tetrahydrofuran-2-yl)-1H-benzo[d]imidaz-
ole could be obtained in 88% yield (entry 5), while 89% yield was
recorded for 1-(1,3-dihydroisobenzofuran-1-yl)-1H-benzo[d]im-
idazole (entry 6). 4,5-Diphenyl-1H-imidazole, a bulky azole, was
also ready to react with tetrahydrofuran to offer 89% yield of 4,5-
diphenyl-1-(tetrahydrofuran-2-yl)-1H-imidazole (entry 7). Al-
though further studies are necessary to elucidate whether the
reaction occurs inside the cavities or on the external surface, the
fact that bulky reactants can provide high yields would indicate
that the transformation would proceed mainly on the external
surface of the catalyst. In the second experiment series, we
conducted the coupling reaction between isochroman with
different azoles, including 1H-1,2,4-triazole, 1H-imidazole, 1H-
imidazo[4,5-b]pyridine, and 1H-imidazo[4,5-c]pyridine. Under
this condition, reasonable yields of the corresponding azole
derivatives were achieved (Table 1).

100

100
80 (a)
80
Transmittance (%)

60
Yield (%)

60
40
40

20
20 (b)

0
0
4000 3600 3200 2800 2400 2000 1600 1200 800 400
1 2 3 4 5 6
-1
Run Wavenumber (cm )

Fig. 12. Catalyst recycling investigations. Fig. 14. FT-IR spectra of the fresh (a) and reused (b) catalyst.
 K.D. Nguyen et al. / Journal of Industrial and Engineering Chemistry 44 (2016) 136145 143

Table 1
The direct CN coupling of different reagents using Fe3O(BPDC)3 catalyst.a

Entry Reactant 1 Reactant 2 Product Isolated yields (%)

1 88

2 92

3 75

4 84

5 88

6 89

7 89

8 72
144 K.D. Nguyen et al. / Journal of Industrial and Engineering Chemistry 44 (2016) 136145
Table 1 (Continued)
Entry Reactant 1 Reactant 2
9 93
10
11
a
Reaction conditions: 80  C, 120 min, 5 mol% catalyst, 3 equivalents of di-tert-butyl peroxide.
Conclusions
In summary, the Fe3O(BPDC)3 was synthesized in compliance
with a marginally modied literature method, and was character-
ized by several techniques. The Fe-MOF could be used as an
effective heterogeneous catalyst for the direct CN coupling of
azoles with ethers via oxidative CH activation to produce azole
derivatives. This MOF-based catalyst expressed higher catalytic
efciency for the synthesis of azole derivatives than that of other
homogeneous iron catalysts and that of other MOFs. The coupling
of azoles with ethers could only progressed in the presence of the
solid Fe-MOF catalyst, and the contribution of leached active iron
species to the formation of the desired azole product, if any, was
insignicant. The catalyst could be reused several times for the
synthesis of azole derivatives without a considerable deterioration
in catalytic efciency. The fact that azole derivatives could be
produced via the direct C-N coupling of azoles with ethers using a
recyclable heterogeneous catalyst should be of signicant benets.
Acknowledgement
We would like to thank the Vietnam National UniversityHo
Chi Minh City (VNU-HCM) for nancial funding under grant
number TX2016-20-05 via annual research program.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.jiec.2016.08.025.
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