Unprecedented salt-promoted direct arylation of acidic sp2 C[sbnd]H bonds under heterogeneous Ni-MOF-74 catalysis: Synthesis of bioactive azole derivatives

Article abstract of DOI:10.1016/j.molcata.2016.11.009

Herein, nickel-based metal-organic framework, Ni-MOF-74, was synthesized by a solvothermal method and its properties was characterized by a host of techniques. Ni-MOF-74 exhibited exceptional catalytic activity toward the direct arylation of azoles via C[sbnd]H activation while other Ni-MOFs, nickel-based heterogeneous systems, and homogeneous counter parts displayed lower activity. Optimal conditions involved the use of Li₂CO₃ or KCl salts in diglyme solvent in 18 h and no additional ligand is required. This is the first and unprecedented report using KCl salt as promoter for arylation of heterocycles. By avoiding the use of strong bases and oxidants, optimized conditions are compatible with wide range of functional groups and heterocycles. Furthermore, by taking advantage of large aperture size of Ni-MOF-74, we are able to utilize optimized conditions to successfully synthesize several bioactive arylated azole derivatives. Previous studies using heterogeneous catalysts to approach these bioactive compounds are not performed in the literature. Leaching tests indicated that homogeneous catalysis via leached active nickel species is unlikely. Thus, the catalyst was facilely separated from the reaction mixture and reused several times without significant degradation of the catalytic reactivity.

Full text of DOI:10.1016/j.molcata.2016.11.009

Accepted Manuscript
Title: Unprecedented salt-promoted direct arylation of acidic
2
sp C-H bonds under heterogeneous Ni-MOF-74 catalysis:
synthesis of bioactive azole derivatives
Author: Huong T.T. Nguyen Duc N.A. Doan Thanh Truong
PII:
S1381-1169(16)30483-6
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.molcata.2016.11.009
MOLCAA 10106
To appear in:
Journal of Molecular Catalysis A: Chemical
Received date:
Revised date:
Accepted date:
22-7-2016
18-10-2016
5-11-2016
Please cite this article as: Huong T.T.Nguyen, Duc N.A.Doan, Thanh Truong,
Unprecedented salt-promoted direct arylation of acidic sp2 C-H bonds under
heterogeneous Ni-MOF-74 catalysis: synthesis of bioactive azole derivatives, Journal
of Molecular Catalysis A: Chemical http://dx.doi.org/10.1016/j.molcata.2016.11.009
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2
Unprecedented salt-promoted direct arylation of acidic sp C-H bonds under
heterogeneous Ni-MOF-74 catalysis: synthesis of bioactive azole derivatives
*
Huong T. T. Nguyen, Duc N. A. Doan, Thanh Truong
Department of Chemical Engineering, HCMC University of Technology, VNU-HCM,
2
68 Ly Thuong Kiet, District 10, Ho Chi Minh City, Viet Nam
*
Email: tvthanh@hcmut.edu.vn
1

Graphic abstract
2

Research Highlights

Our work provides the unprecedented and general heterogeneous Ni-MOFs-catalyzed direct
arylation of heterocycles using KCl as promoter.


First report using heterogeneous catalysts to approach bioactive azole derivatives.
The catalyst could be recovered and reused.
3

Abstract
Herein, nickel-based metal-organic framework, Ni-MOF-74, was synthesized by a solvothermal
method and its properties was characterized by a host of techniques. Ni-MOF-74 exhibited
exceptional catalytic activity toward the direct arylation of azoles via C-H activation while other
Ni-MOFs, nickel-based heterogeneous systems, and homogeneous counter parts displayed lower
activity. Optimal conditions involved the use of Li CO or KCl salts in diglyme solvent in 18
2
3
hours and no additional ligand is required. This is the first and unprecedented report using KCl
salt as promoter for arylation of heterocycles. By avoiding the use of strong bases and oxidants,
optimized conditions are compatible with wide range of functional groups and heterocycles.
Furthermore, by taking advantage of large aperture size of Ni-MOF-74, we are able to utilize
optimized conditions to successfully synthesize several bioactive arylated azole derivatives.
Previous studies using heterogeneous catalysts to approach these bioactive compounds are not
performed in the literature. Leaching tests indicated that homogeneous catalysis via leached
active nickel species is unlikely. Thus, the catalyst was facilely separated from the reaction
mixture and reused several times without significant degradation of the catalytic reactivity.
Keywords: Metal-organic framework; C-H arylation; heterogeneous catalyst; Ni-MOF-74;
bioactive azoles
1
. Introduction
Metal-promoted arylation of heterocycle compounds using direct C-H activation has increasingly
gained attention [1, 2]. By using C-H bonds as starting materials, the method provides shorter
and more efficient synthetic approach than the conventional cross-coupling methods such as the
Suzuki–Miyaura, Stille, Negishi and other named reactions. This further improves atom-
economical and environmental issues of synthetic procedures [3-5]. Previous works on arylation
4

of heteroarenes with aryl electrophiles through direct C-H functionalization involved the use of
palladium-, rhodium-, ruthenium-, or iridium-based catalyst systems [6-13]. More recently,
efforts geared toward the use of non-noble metal catalysts have been witnessed in the synthetic
community [14]. Specifically, a significant breakthrough on the copper-catalyzed direct
heterocycle C-H arylation reaction of various heteroarenes with haloarenes using copper salts as
catalysts was investigated by Daugulis group [2, 15], nickel-based catalysts have emerged as
promising candidates for organic transformations through direct C-H activation [16]. Miura and
co-workers discovered that the combination of NiBr and nitrogen-containing compounds such
2
as 2,2’-bipyridine (bipy) or 1,10-phenanthroline as ligands could offer high activity for the direct
coupling of azole derivatives and organoboronic acids [17]. Ni(OAc) /bipy has been established
2
by Itami as an efficient catalytic protocol for the arylation of heteroarenes with aryl halides and
triflates [18]. Lei and co-workers demonstrated a novel oxidative arylation of cyclic ethers with
arylboronic acid employing Ni(acac) as catalyst precursor in the presence of triphenylphosphine
2
(
PPh ) as the ligand and di-tert-butyl peroxide as the oxidant [19]. Under the demand of the
3
pharmaceutical and other chemical industries, heterogeneous catalytic systems for direct
arylation of heteroarenes were recently disclosed [20]. However, in most cases, palladium-based
catalysts were employed or strong bases or oxidants were required for depronation/activation of
C-H bonds. Additionally, protocols for bulky bioactive compound synthesis are not disclosed
yet. Therefore, the development of milder and more practical processes using heterogeneous
catalysts, especially in pharmaceutical industry, should be targeted [21].
Although the application of MOFs in catalysis has just been investigated for the past few years,
MOFs have been showed to possess high activity for a variety of organic transformations [22-
5

2
6]. Though Cu-based MOFs have been frequently utilized as efficient heterogeneous catalysts,
nickel-based MOFs have been rarely reported. In particular, Kim and Chou group disclosed the
nickel nanoparticles supported on MOF as heterogeneous for hydrogenation reactions [27, 28].
Recently, Jiang and co-workers employed nickel(salphen)-based MOF as a heterogeneous
catalyst for the synthesis of cyclic carbonates [29]. We reported the first nickel-catalyzed direct
heterocycle C-H arylation reaction under Ni (BDC) (DABCO) (H BDC= benzene-1,4-
2
2
2
dicarboxylic acid, DABCO = 1,4-diazabicyclo[2.2.2]octane) catalysis [30]. However, synthetic
protocol involved the use of pre-functionalized arylboronic acids, strong base, and was only
applicable for benzoxazoles. Furthermore, the optimal conditions failed to synthesize bulky
bioactive compounds. Recently, the discovery of MOF-74 with paddle wheel structure, open
metal sites, high coordinate metal ion, and pore apertures are of a size suitable for the inclusion
of large organic molecules offered a promising type of MOFs, especially for pharmaceutical
industry [31-33]. Herein, we report an efficient route for arylation of azoles via C-H activation
over Ni-MOF-74 catalyst using inexpensive and air stable Li CO or KCl salts as promoters. This
2
3
is the first report using KCl salt as promoter for arylation of heterocycles. Interestingly, the use
of large pore size Ni-MOF-74 allowed the efficient synthesis of bioactive arylated oxazoles.
2
. Experimental
2
.1. Materials and instrumentation
Unless otherwise noted, all materials including dry solvents were obtained from commercial
suppliers such as Acros Organics, Sigma–Aldrich and Merck and used as received. All coupling
reactions were performed under an atmosphere of Argon gas in dried 8 mL vials, used 7 x 2 mm
spinbar and heated in a 34–well reaction block Optochem heater. Monitoring experiments by gas
6

chromatography (GC) was performed with 10 mm vials equipped with caps, septa. Activation
and purification procedures were carried out by using Schlenkline system. Nitrogen
physisorption measurements were conducted using a Micromeritics 2020 volumetric adsorption
o
analyzer system. Samples were pretreated by heating under vacuum at 150 C for 3 h. A Netzsch
Thermoanalyzer STA 409 was used for thermogravimetric analysis (TGA) with a heating rate of
o
1
0 C/min under a nitrogen atmosphere. X-ray powder diffraction (XRD) patterns were recorded
using a Cu Kα radiation source on a D8 Advance Bruker powder diffractometer. Scanning
electron microscopy studies were conducted on a S4800 Scanning Electron Microscope (SEM).
Transmission electron microscopy studies were performed using a JEOL JEM 1400
Transmission Electron Microscope (TEM) at 100 kV. The Ni (BDC) (DABCO) sample was
2
2
dispersed on holey carbon grids for TEM observation. Elemental analysis with atomic absorption
spectrophotometry (AAS) was performed on an AA-6800 Shimadzu. Fourier transform infrared
(FT-IR) spectra were obtained on a Nicolet 6700 instrument, with samples being dispersed on
potassium bromide pallets.
Gas chromatographic (GC) analyses were performed using a Shimadzu GC 2010-Plus equipped
with a flame ionization detector (FID) and an SPB-5 column (length = 30 m, inner diameter =
0
.25 mm, and film thickness = 0.25 μm). The temperature program for GC analysis heated
o
o
o
o
samples from 120 to 130 C at 40 C/min; heated from 130 to 180 C at 40 C/min and held them
o
o
o
o
at 180 C for 0.5 min; heated them from 180 to 280 C at 50 C/min and held them at 280 C for
o
5
min. Inlet and detector temperatures were set constant at 280 C. n-Hexadecane was used as an
internal standard to calculate reaction conversions. GC-MS analyses were performed using a
Hewlett Packard GC-MS 5972 with a RTX-5MS column (length = 30 m, inner diameter = 0.25
mm, and film thickness = 0.5 μm). The temperature program for GC-MS analysis heated samples
7

o
o
o
from 60 to 280 C at 10 C/min and held them at 280 C for 5 min. Inlet temperature was set
o
1
constant at 280 C. MS spectra were compared with the spectra gathered in the NIST library. H
1
3
and C NMR spectra were recorded in CDCl using TMS as an internal standard on a Bruker
3
NMR spectrometer at 500 MHz and 125 MHz, respectively.
2
.2. Synthesis of the metal-organic framework Ni-MOF-74
In a typical preparation [34, 35], a solution of 2,5–dihydroxyterephthalic acid (0.102 g, 0.5
mmol) in 7.5 mL of THF and a solution of nickel acetate tetrahydrate (0.252 g, 1 mmol) in 7.5
mL of water were added into 15 mL pressure tube. The tube was capped and mixture was stirred
o
at room temperature for 15 minutes before being placed in oven at 120 C for 24 hours. After
cooling to room temperature, the mother liquor was decanted and the solid product was washed
by THF three times (3 x 10 mL) each day for 3 days. The products were then dried under
o
reduced pressure at 140 C in 8 hours. The sample was cooled to room temperature, yielding
0
.1633 g of Ni-MOF-74 in the form of yellow fined–crystalline substance (94 %).
2
.3. Catalytic studies
In a typical experiment, a predetermined amount of Ni-MOF-74 was added to the 8 mL vial
containing a mixture of iodobenzene (0.1030 g, 0.5 mmol), benzothiazole (0.1379 g, 1.0 mmol),
Li CO or KCl (1.0 mmol), and diphenyl ether (0.085 g, 0.5 mmol) as standard. 1–Methoxy–2–
2
3
(2–methoxyethoxy)ethane (diglyme) (1 mL) was added and vial was tightly capped. Reaction
o
mixture was heated at 160 C for 24 hours. The catalyst loading was based on the molar ratio of
nickel/iodobenzene. The reaction yield was monitored by withdrawing aliquots from the reaction
mixture at different time intervals, diluting with ethylacetate (2 mL), quenching with an aqueous
KOH solution (1%, 1 mL), and then drying over anhydrous Na SO before analyzing by GC with
2
4
8

reference to diphenyl ether (internal equation with pure product), and further confirming product
identity by GC–MS and NMR. To investigate the recycle ability of Ni-MOF-74, the catalyst was
filtered from the reaction mixture after the experiment, washed with ethylacetate, water, THF,
o
and dried at 140 C under vacuum in 8 hours. For the leaching test, a catalytic reaction was
stopped after 12 hours, analyzed by GC, and filtered to remove the solid catalyst. The reaction
solution was then stirred for a further 12 h. Reaction progress, if any, was monitored by GC as
previously described.
3
. Results and discussion
3
.1. Catalyst synthesis and characterization
In this work, the Ni-MOF-74 was synthesized in a yield of 94 % by a solvothermal method,
according to a slightly modified literature procedure [34, 35]. Its structural properties were
characterized by a variety of different techniques, including XRD, SEM, TEM, TGA, FT-IR,
AAS, and nitrogen physisorption measurements (Fig. S12 – Fig. S18). The analysis results were
in agreement with previous studies [35]. These confirmed that the synthesized Ni-MOF-74
possesses paddle wheel structure, open metal sites, and exceptionally large pore apertures.
Specifically, powder X-ray diffraction pattern showed the typical reflections of MOF-74 phase.
The basically type-1 adsorption/desorption isotherm indicated the permanent micro-porosity with
2
3
Brunauer–Emmett–Teller specific surface area of 889 m /g, a pore volume of 0.41 cm /g and an
average pore diameter of about 16 Å. Scanning electron microscopy analysis showed the
homogeneity. Thermal gravimetric analysis (TGA) of activated Ni-MOF-74 shows high thermal
stability (>300 °C) and the measured mass percent of residue NiO is consistent with the EA data.
AAS provided 33.3 % copper content which is close to the calculated value of 34.2 %. Finally,
FT-IR spectra of Ni-MOF-74 indicated the presence of bonded carboxylate organic linkers.
9

3
.2 Catalytic studies
It is worth mentioning that in previous report using homogeneous Ni(OAc) catalysts, bidentate
2
t
ligand was required to obtain good yields [18]. In addition, air-sensitive BuOLi base was
employed under inert atmosphere [18, 19]. Under the industrial view of point, synthetic protocols
without homogeneous ligands, strong bases, and under atmospheric conditions are highly
needed. Within this study, we aim to develop more simple and practical procedure without added
ligands and using bench-top reagents. We hypothesized that Li CO /diglyme would promote the
2
3
arylation of azoles on the basis of following considerations: (1) strong binding constant of of Li
cation in diglyme solvent due to high coordination of Li with oxygen atom [36], (2) σ-adduct
formation at the metal center is favored by the carboxylate anion [37, 38, 39].
In reaction screening, the catalytic activity of Ni-MOF-74 was investigated in the direct arylation
of benzothiazole using iodobenzene as coupling partner (Table 1). Gratifyingly, with respect to
amount of catalyst, 90 % GC yield was obtained when 10 % catalyst was employed (entry 3).
Decreasing amount of catalyst led to significant drop in reaction yields (entries 1, 2) while no
further improvement was obtained when amount of catalyst was increased (entry 4). Solvents
such as mesitylene, dimethylformamide (DMF), dimethyl propylene urea (DMPU), dimethyl
sulfoxide (DMSO), and N-methyl-2-pyrolidone (NMP) are not suitable under tested conditions
when < 6 % yield was achieved (entries 5-9). Reactions in dimethylacetamide (DMA) afforded
only 24 % (entry 10). This confirmed the synergetic effect of Li CO /diglyme system.
2
3
Optimization of reagent ratios and reaction concentration indicated that using 2 equivalents of
iodobenzene at 0.5 M was optimal (entries 11-14).
1
0

a
Table 1. Condition optimization
Amount of
Entry
Temperature
Ratio
y/x
Solvent
GC yield (%)
o
catalyst (%)
( C)
1
2
3
4
5
6
7
8
9
5
Diglyme
Diglyme
Diglyme
Diglyme
160
160
160
160
160
160
160
160
160
160
140
150
160
160
160
160
160
160
2
2
58
75
90 (89)
87
<2
<2
<2
6
7.5
10
12.5
10
10
10
10
10
10
10
10
10
10
10
10
10
10
2
2
Mesitylene
DMF
2
2
DMPU
2
DMSO
2
NMP
2
4
1
0
DMA
2
24
10
36
32
89
6
1
1
2
3
4
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
2
1
1
1
2
1.5
2.5
2
b
1
5
6
c
1
1
1
2
81
84
d
7
2
e
8
2
81
a
b
c
d
Li CO (2 equiv.), 1.0 mmol scale, 0.5 M, 18 h. Reaction at 0.25 M. Reaction at 0.75 M. Reaction using 2.5
2
3
e
equiv. of base. Reaction using 1.5 equiv. of Li CO Numbers in parentheses indicate the isolated yields. Kinetic
2
3
studies of reaction temperature were placed in Supporting Information.
It was reported that pKa of benzothiazole in DMSO was about 30 [40] while pKa of Li CO was
2
3
estimated to be about 10 [41]. To further invesitgate the special role of Li CO , several control
2
3
experiments using a variety of bases were conducted (Table 2). Remarkably, replacing Li CO by
2
3
stronger carbonate bases such as Na CO K CO and Cs CO which were commonly used in
2
3,
2
3,
2
3,
1
1

previous studies of cross coupling reactions, completely retarded the reactions (entries 2-4).
Undetectable amount of desired product was observed when benzothiazole was arylated using
K PO (entry 5). Tert-butoxide bases which were employed in homogeneous protocols were
3
4
showed to be inactive (entries 6, 7). These results confirm the combinatory roles of lithium
cation and carbonate anion in diglyme media. The hypothesis was supported by the inefficiency
of LiNO Li SO LiOH, and LiHCO bases (entries 8-11). Unprecedentedly, substantial amount
3
,
2
4,
3
of desired product was observed when LiCl, NaCl, or KCl was employed instead of Li CO In
2
3.
particular, up to 91 % yield was obtained with KCl promoter while undetected amount of product
was obtained in the absence of KCl. Though it is well recognized that diglyme possesses great
ability to chelate small cations and make anion more active [42], studies on KCl/diglyme system
for depronation has not been reported. Furthermore, addition of frequently used ligands in
previous homogeneous studies shut down the reaction when either Li CO or KCl was utilized.
2
3
This could be rationalized by the fact that the added ligands might occupy the open site of nickel
by coordination. Unlike homogeneous counterpart, association of ligand in MOFs can
permanently saturate the metal center [43].
Table 2. Effect of various bases to reaction yields.
a
Entry
Additive
Li CO
Added ligand
GC Yield
1
2
-
-
90
<2
2
3
Na CO
2
3
1
2

3
4
5
6
7
8
9
K CO
-
<2
<2
<2
4
2
3
Cs CO
-
2
3
K PO
-
3
4
t
BuOLi
-
t
BuONa
-
<2
<2
<2
<2
<2
66
81
91
<2
<2
<2
<2
LiHCO3
LiNO3
LiOH
-
-
1
0
1
2
-
1
1
Li SO
-
2
4
LiCl
-
NaCl
KCl
-
-
1
3
-
-
1
1
1
4
5
6
KCl or Li CO
1,10-phenanthroline
TMEDA
2
3
KCl or Li CO
2
3
KCl or Li CO
2
3
2,2-bipyridine
a
1
.0 mmol scale, 0.5 M.
To gain more insights about interaction of diglyme, experiments using various etheral solvents
with different chelating affinity were conducted using KCl as additive (Table 3). Interestingly,
decreasing the chelating affinity of sovent by using solvents containing less oxygen atoms
resulted in an significant drop in reaction rate (entries 2, 3). Specifically, reactions using
monoglyme afforded 47 % yields while solvent containing one oxygen atom (dibutyl ether) was
inactive. Moreover, only 57 % yield was observed when triglyme was employed (entry 4). 18-
Crown-6, which is known to possess exceptionally high affinity for potassium cation, completely
inhibited the reactions. Similar results was obtained when 12-crown-4 solvent and Li CO were
2
3
used. These data could be rationalized by the occupacy of open nickel site by strong chelating
solvents.
1
3

Table 3. Reactions with various ether solvents
a
Entry
1
Sovent
GC Yield
91 (90)
Diglyme
a
Monoglyme
dimethoxyethane)
2
47 (38)
<2
(
3
4
5
Dibutyl ether
Triglyme (triethylene
glycol dimethyl ether)
57 (62)
18-Crown-6
<2
<2
b
6
12-Crown-4
o
Reaction conditions: Ni-MOF-74 (10 %), KCl (2 equiv.), 160 C, 18h, 1
mmol scale, 0.5 M, iodobenzene/benzothiazole = 2/1. Numbers in
a
parentheses indicate GC yields when Li CO was employed. Reactions in
2
3
b
pressure vessel. Reactions using Li CO
2
3.
To highlight the activity of Ni-MOF-74, reactions using frequently used catalysts for organic
transformations were carried out under optimized conditions (Table 4). Notably, removing the –
OH group in the linker, Ni-BDC, resulted in significant drop in catalytic activity even with added
ligands (entries 2, 3). Remarkably lower conversions were obtained with Ni (BTC) (H BTC =
3
2
3
benzene-1,3,5-tricarboxylic acid) and Ni(HBTC)(BPY) (BPY = 4,4′-bipyridine) with 4 % and 12
, respectively (entries 4, 5). All tested Ni-MOFs contain open metal sites and possess similar
%
surface areas. High reactivity of Ni-MOF-74 could be rationalized by the aperture size and the
additional coordination of –OH group in Ni center. In addition, the use of Ni-MOF-74 is
technically preferred for the synthesis of other product derivatives which often have bulk size.
It is worth mentioning that heterogeneous Ni-based mesoporous or magnetic nano particle
catalysts were showed to be unsuitable (entries 6-8). Other transition-metal-based organic
frameworks such as Cu-MOF-74 Zn-MOF-74 or Co-MOF-74 are not effective and
,
unappreciable amount of product was observed (entries 9-11). This observation confirms the
1
4

necessity of nickel metal site in MOFs structure. It is worth mentioning that as compared to
homogeneous counter-parts, traditional heterogeneous catalysts often provide lower activity.
However, in this report, heterogeneous Ni-MOF-74 possesses similar or better activity than other
tested Ni salts which were frequently used as homogeneous catalysts in typical cross-coupling
reactions (entries 12-16).
Table 4. Reactivity of other catalysts
GC yield
Entry Type
Catalyst (10 %)
Linker (acid)
(%)
1
2
Ni-MOF-74
Ni-BDC
2,5–dihydroxyterephthalic
terephthalic
91
52
61
12
4
3
4
5
6
7
8
9
1
1
1
1
1
1
1
Ni (BDC) (DABCO)
terephthalic
Heterogeneous
Ni-based
2
2
Ni(HBTC)(BPY)
1,3,5-benzenetricarboxylic
1,3,5-benzenetricarboxylic
catalysts
Ni (BTC)2
3
NiFe O4
32
15
31
3
2
Ni/Zeolite X
Ni/ZSM-5
MOF-74-Cu
MOF-74-Co
MOF-74-Zn
Ni(OAc)2
NiSO4
2,5–dihydroxyterephthalic
2,5–dihydroxyterephthalic
2,5–dihydroxyterephthalic
0
1
2
3
4
5
6
Other MOFs
<2
4
82
81
84
80
<2
Homogeneous
Ni(II) salts
Ni(NO3)2
NiBr2
NiCl2
a
o
1
.0 mmol scale, 160 C. 0.5 M, iodobenzene/benzothiophen = 2/1.
1
5

100
80
60
40
20
0
7
mol% catalyst
Leaching test
0
4
8
12
16
20
24
Time (h)
Fig. 1. Leaching test
In leaching test, a control experiment was carried out using a simple hot filtration during the
course of the reaction (Fig. 1). The direct coupling reaction was conducted under optimal
o
conditions involving the use of KCl salt (2 equiv.) in diglyme solvent at 160 C in 24 hours.
After 12 hours with 42 % yield being detected, the Ni-MOF-74 catalyst was removed from the
reaction mixture by hot filtration. The liquid phase was then transferred to a new reactor vessel,
and magnetically stirred for an additional 12 hours with aliquots being sampled at different time
intervals, and analyzed by GC. It was observed that no further conversion was detected in the
reaction mixture after the Ni-MOF-74 catalyst was separated from the reaction mixture (Fig. 2).
In addition, ICP-MS revealed less than 1 ppm of nickel in the filtrate from reaction mixture.
Therefore, it is likely that reactions could only proceed in the presence of the solid Ni-MOF-74
catalyst, and there should be no contribution from leached active nickel species in the liquid
phase.
1
6

100
80
60
40
20
0
1
2
3
4
5
6
Run time
Fig. 2. Catalyst recycling studies.
The recoverability and reusability of the Ni-MOF-74 catalyst were investigated by repeatedly
separating the solid catalyst from the reaction mixture after the reaction (Fig. 2). The cross
o
coupling reactions was carried out using 2 equiv. of KCl in diglyme at 160 C for 24 hours, in
the presence of 10 mol% Ni-MOF-74 catalyst. After the experiment, the Ni-MOF-74 catalyst
was separated from the reaction mixture by simple centrifugation, washed with copious amounts
o
of ethylacetate, water and THF, dried at 140 C under vacuum in 8 hours and reused in further
reactions under identical conditions to the first run. It was found that the Ni-MOF-74 catalyst
could be recovered and reused several times without a significant degradation in catalytic
th
activity. Indeed, a yield of 87 % was still achieved in the 6 run. As compared to the FT-IR
result of the fresh catalyst, the spectra of reused Ni-MOF-74 exhibited a similar absorption (Fig.
4
). Moreover, the XRD result of the recovered Ni-MOF-74 indicated that the crystallinity could
be maintained (Fig. 3).
1
7

1
2000
0000
1
8000
6000
4000
2000
0
b)
a)
5
10
15
20
25
30
2-Theta scale
th
Fig. 3. X-ray powder diffractograms of fresh Ni-MOF-74 catalyst (a) and the 6 re-used (b).
(b)
(a)
Fig. 4. FT-IR spectra of fresh Ni-MOF-74 catalyst (a) and the reused (b).
To preliminary address the issue of where the catalysis occurs, experiments using grinded Ni-
MOF-74 were conducted under identical conditions (Fig. 5). It was observed that similar reaction
1
8

conversions were obtained during the reaction course in both cases. In addition, the cavity size
according to the Ni-MOF-74 structure is about 15-17 Å while the kinetic diameters of aromatic
o
o
reactant and product are calculated to be 7.1 A and 10.5 A, respectively [44]. Furthermore, pore
flexibility in MOFs upon temperature and guest molecules has been previously reported [45].
Though it is likely that reactions take place inside the catalyst pores, further spectroscopic
studies are still needed.
100
80
60
40
20
0
non-grinded Ni-MOF-74
grinded Ni-MOF-74
0
4
8
12
Time (h)
16
20
24
Fig. 5. Reactions with grinded Ni-MOF-74
The generality of optimal conditions using Ni-MOF-74 on other derivatives of coupling
components were described in Table 5. Functionality occurs at most acidic C-H bonds in all
cases. Reaction at larger scale and reaction with added (2,2,6,6-tetramethylpiperidin-1-
yl)oxidanyl (TEMPO) gave similar results (entries 1b, 1c). Aryl halides with electron donating
groups such as methyl and methoxy are active and cross coupling products were achieved in
reasonable yields (entries 2, 3). Arylation using iodobenzene containing electron withdrawing
groups (ketone, nitro, ester) is also possible and C2-arylated benzothiazole was obtained in
1
9

excellent yields (entries 4-6). Reported procedures using strong bases were not compatible with
these functional groups [18, 19]. Selective mono-arylation of 1,4-diiodobenzene could be done
(entry 7). Optimized conditions are also applicable for aryl halides with substituents at ortho or
meta-position (entries 8, 9). With respect to heterocycles, reactions is not only limited to
benzothiazole. In particular, good yields were achieved for arylation of 4,5-dimethylthiazole,
benzoxazole, 1-methylimidazole, and caffeine (entries 10-12). It is worth mentioning that
previous reported conditions using Cu-MOFs catalysts for arylation of heterocycles were only
active for benzoxazole [46].
Table 5. Reactions scope of coupling components
Yields
Entry
1
Heterocycle
Aryl halides
Product
(
%)
8
9,
b
8
7 ,
c
8
8
d
8
0
2
3
4
5
50
5
3
d
4
1
87
55
2
0

6
7
80
32
47
8
9
9
7
d
8
2
1
0
1
52
97
1
1
2
38
b
c
Conditions: Diglyme (4 mL), heterocycles (0.5 mmol), 18 h. 5 mmol scale. Reaction with added
d
TEMPO (10 %). Reaction using bromoarenes
Under pharmaceutical viewpoint, the use of homogeneous catalysts often represents a major
problem regarding purification of contaminated metals in final products, further increase the cost
of entire process [47]. To further expand on the potential of Ni-MOF-74 to be used in practical
applications, we utilized this heterogeneous catalyst in the synthesis of pharmaceutically relevant
oxazoles possessing bioactivity (Scheme 2). In particular, Texamine, an alkaloid isolated from
2
1

roots of amyris texana and possessing mitoinhibitory properties [48], was obtained in 71 % yield
under Ni-MOF-74 catalysis via direct arylation of 5-(1,3-benzodioxol-5-yl)oxazole. Balsoxin, an
antimycobacterial agent which was reported to be constructed by 7 steps, was achieved in 26 %
yield [49]. Similarly, optimized conditions were successfully utilized to synthesize bioactive
unguenenazole in good yield [50]. The reaction conditions are not limited to oxazole derivatives.
Bioactive arylated benzothiazoles such as 4-(benzothiazol-2-yl)phenol and 2-(thiophen-2-
yl)benzothiazole were obtained in acceptable yields under optimized conditions. These
compounds were showed to serve as multifunctional vasodilators on rat artery and possess
antidiabetic potential [51, 52]. In addition, 2-styryl-1-methylbenzimidazole, an inhibitor of
monoamine oxidase B (MAO-B) [53], was also obtained by arylation of 1-methylbenzimidazole
using 1-iodo-2-phenylethene. It is noted that these compounds were not previously synthesized
using heterogeneous catalysts. One can argue that increasing efficiency in such reactions makes
the chemical processes more "green" by recycling the catalysts and reducing the amount of steps
in the purification.
2
2

Scheme 2. Synthesis of bioactive compounds using the heterogeneous Ni-MOF-74 catalyst.
4
. Conclusions
In brief, we have described a practical method for salt-promoted arylation of wide range of
heterocycles under heterogeneous Ni-MOF-74 catalysis. The optimal reaction conditions involve
the use of KCl or Li CO salts in diglyme solvent at 160 °C in 18 hours. For the first time, KCl
2
3
salts was used as efficient promoter for arylation of acidic heterocycles. The method is
advantageous compared to the existing routes by avoiding the utilization of strong bases and
soluble ligands, which has not been previously described under heterogeneous catalytic systems.
Subsequently, the substrate scope of Ni-MOF-74 was demonstrated to be widely applicable to
various substituted aryl halides and heterocycles. The first synthesis of bioactive azole
compounds under heteterogeneous catalyst was also described. Interestingly, Ni-MOF-74
exhibited higher catalytic activity than other Ni-based heterogeneous catalysts and homogeneous
nickel salts. In addition, Ni-MOF-74 were showed to be recovered and reused several times
2
3

without a significant degradation in catalytic activity and contribution from homogeneous
leached active copper species, if any, is negligible.
Acknowledgements
Vietnam National University – Ho Chi Minh City (VNU-HCM) is acknowledged for financial
support via grant No. B2015-20-04. Huong T. T. Nguyen is grateful to HCMC University of
Technology, VNU-HCM via grant No. TSĐH-2015-KTHH-05
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