A new route to triphenylpyridines utilizing ketoximes as building blocks via cascade reactions under iron-organic framework catalysis

Article abstract of DOI:10.1002/aoc.4841

Iron-based metal–organic framework VNU-20 was utilized as a heterogeneous catalyst for cascade reactions between ketoximes and dibenzyl ether to produce 2,4,6-triphenylpyridines. Additionally, benzyl alcohol and (dimethoxymethyl)benzene could be used as an alternative starting materials for the transformation. The oxidant exhibited a remarkable impact on the reactions, and di-tert-butylperoxide was the most appropriate candidate. The VNU-20 displayed higher efficiency than many homogeneous and heterogeneous catalysts. The catalyst was reusable for the cascade reactions without a noticeable deterioration in catalytic activity. This transformation is new, and would offer alternative routes to triphenylpyridines utilizing ketoximes as building blocks.

Full text of DOI:10.1002/aoc.4841

Received: 31 August 2018
DOI: 10.1002/aoc.4841
Revised: 7 January 2019
Accepted: 8 January 2019
F U L L P A P E R
A new route to triphenylpyridines utilizing ketoximes as
building blocks via cascade reactions under iron‐organic
framework catalysis
1
1
1
1
1
Vu H.H. Nguyen | Son H. Doan | Tram T. Van | Phuc H. Pham | Tran T.N. Nguyen |
2
2
1
Ngoc N. Nguyen | Thach N. Tu
| Nam T.S. Phan
1
Faculty of Chemical Engineering, HCMC
Iron‐based metal–organic framework VNU‐20 was utilized as a heterogeneous
catalyst for cascade reactions between ketoximes and dibenzyl ether to produce
,4,6‐triphenylpyridines. Additionally, benzyl alcohol and (dimethoxymethyl)
benzene could be used as an alternative starting materials for the transforma-
tion. The oxidant exhibited a remarkable impact on the reactions, and di‐tert‐
butylperoxide was the most appropriate candidate. The VNU‐20 displayed
higher efficiency than many homogeneous and heterogeneous catalysts. The
catalyst was reusable for the cascade reactions without a noticeable deteriora-
tion in catalytic activity. This transformation is new, and would offer alterna-
tive routes to triphenylpyridines utilizing ketoximes as building blocks.
University of Technology, VNU‐HCM, 268
Ly Thuong Kiet, District 10, Ho Chi Minh
City, Viet Nam
2
2
Center for Innovative Materials and
Architectures, VNU‐HCM, Quarter 6,
Linh Trung Ward, Thu Duc District, Ho
Chi Minh City, Viet Nam
Correspondence
Nam T. S. Phan, Faculty of Chemical
Engineering, HCMC University of
Technology, VNU‐HCM, 268 Ly Thuong
Kiet, District 10, Ho Chi Minh City, Viet
Nam.
Email: ptsnam@hcmut.edu.vn
KEYWORDS
alcohols, cascade reaction, ethers, ketoximes, metal–organic framework, Triphenylpyridines
1
| INTRODUCTION
by using a FeCl ‐catalyzed coupling of ketoximes with N,
3
[
9]
N‐dialkylanilines. Yi et al. developed a FeCl ‐catalyzed
3
Substituted pyridines have been well recognized as ubiqui-
tous scaffolds, usually found in a wide range of naturally
occurring bioactive molecules and synthetic organic struc-
tures with precious medicinal and pharmaceutical proper-
cyclization transformation between benzaldehydes and
[
10]
ketoximes to produce 2,4,6‐triphenylpyridines.
Indeed,
ketoximes and their derivatives have recently been consid-
ered as praiseworthy building blocks for many precious
organic structures, and expanding the application of
ketoximes in organic chemistry still remains to be
[
1–4]
ties.
Among numerous pyridine derivatives, 2,4,6‐
triphenylpyridines have received attention, and significant
efforts have been devoted to the synthesis of these valuable
heterocycles. Tan et al. previously reported a copper
complex‐catalyzed condensation of ketoximes with
[
9,11–15]
explored.
The last two decades have witnessed a rapid develop-
ment of research on metal–organic frameworks (MOFs),
a notable class of highly crystalline polymeric materials,
self‐assembled from organic linkers with metal ions or
[
5]
ketimines to produce highly substituted pyridines.
Xiang et al. demonstrated an iodine‐mediated synthesis
of 2,4,6‐triphenylpyridines from amino acids and
[
16–19]
metal clusters.
Owing to their diverse porous struc-
[6]
acetophenones. Zhang et al. developed an efficient pro-
tures with various connectivity and symmetry, MOFs
have been extensively explored for applications in numer-
ous fields, ranging from adsorption to biomedical engi-
tocol to achieve 2,4,6‐triphenylpyridines from ketones
[7]
and amines using HOTf catalyst. Ren et al. synthesized
[
20–22]
2
,4,6‐triphenylpyridines via a CuBr‐catalyzed coupling of
neering.
Highlighted by permanent porosity,
[8]
ketomixes with aldehydes. Zhao et al. consequently
adjustable internal surface functionality, and concen-
trated active sites, MOFs have emerged as promising
extended this protocol to obtain 2,4,‐diphenylpyridines
Appl Organometal Chem. 2019;e4841.
wileyonlinelibrary.com/journal/aoc
© 2019 John Wiley & Sons, Ltd.
1 of 11
https://doi.org/10.1002/aoc.4841

2
of 11
NGUYEN ET AL.
candidates for catalysis. 23–25] Catalytically active sites
could be generated on both organic and inorganic compo-
nents in the framework, therefore offering significant
[
GC–MS, H NMR, and C NMR. For the catalyst reuti-
lizing studies, the VNU‐20 was separated by centrifuga-
tion, washed thoroughly with DMF and methanol, dried
under vacuum on a Schlenkline at room temperature,
and reused for next experiment.
1
13
[
26–28]
advantages over conventional catalytic materials.
In addition to MOFs consisted of a single kind of organic
ligand, many frameworks constructed from a mixture of
[29–31]
two or more linkers have also been studied.
Among
3
| RESULTS AND DISCUSSION
.1 | Catalyst synthesis and
a long list of frameworks, iron‐based MOFs have gained
[
32–34]
considerable interests.
Certainly, diverse organic
3
transformations were previously conducted under
Fe‐MOF catalysis conditions.
[35–37]
characterization
In this work, we
would like to present alternative routes to 2,4,6‐tripheny-
lpyridines from ketoximes and dibenzyl ether via cascade
reactions in the presence of VNU‐20 iron‐organic frame-
work catalyst. Additionally, benzyl alcohol and (dime-
thoxymethyl)benzene could be used as an alternative
starting materials for the transformation. This protocol
was not previously reported in the literature, and would
be complementary to previous methods in the synthesis
of these valuable heterocycles.
Utilizing solvothermal method, the VNU‐20 was pro-
duced in 71% yield from 2,6‐napthalenedicarboxylic acid,
[38]
1,3,5‐benzenetricarboxylic acid, and iron (II) chloride.
The iron‐organic framework was subsequently character-
ized by using several traditional analysis protocols
(
Figure S1 – Figure S7). X‐ray powder diffraction patterns
of the VNU‐20 with sharp peaks being recorded verified
that a crystalline framework was generated (Figure S1).
Additionally, scanning electron microscopy observation
exhibited the crystal character of the Fe‐MOF (Figure
S2). Transmission electron microscopy analysis displayed
a porous structure for the framework, though pore struc-
tures were elaborate (Figure S3). Nitrogen physisorption
measurements displayed that the Fe‐MOF contained
microporous pores with diameter of less than 20 Å being
2
| EXPERIMENTAL
The VNU‐20 was synthesized from 2,6‐napthalenedi-
carboxylic acid, 1,3,5‐benzenetricarboxylic acid, and iron
[38]
(
II) chloride by following a literature procedure.
typical experiment, dibenzyl ether (0.020 g, 0.10 mmol),
E)‐1‐phenylethan‐1‐one O‐acetyl oxime (0.0708 g, 0.4
In a
noted (Figure S4). Moreover, Langmuir surface areas of
2
7
60 m /g were noticed for the iron‐based framework, as
(
estimated from nitrogen adsorption/desorption isotherm
data (Figure S5). The most notable characteristic in the
thermogravimetric analysis result for the VNU‐20 was
that small weight loss was noticed for the temperature
range of 200–350 °C, verifying the generation of a stable
phase in the framework (Figure S6). Additionally, Fourier
transform infrared spectra of the VNU‐20 was different to
those of 2,6‐napthalenedicarboxylic acid and 1,3,5‐
benzenetricarboxylic acid (Figure S7).
mmol), and diphenyl ether (0.034 g, 0.20 mmol) as an
internal standard were dissolved in chlorobenzene
(1 mL), and the solution was then added to a pressurized
vial containing the VNU‐20 catalyst. Subsequently,
di‐tert‐butylperoxide (DTBP; 0.037 ml g, 0.30 mmol) as
oxidant was added dropwise to the vial. The mixture
was consequently heated with magnetic stirring at
1
40 °C for 6 h under an argon atmosphere. Reaction
yields were monitored by GC analysis concerning the
diphenyl ether internal standard. After the reaction was
complete, ethyl acetate (30 mL) was added to the vial.
The reaction mixture was washed with HCl solution (5%
in water, 3 x 5 ml), and subsequently with saturated
3.2 | Catalytic studies
The VNU‐20 was utilized as a heterogeneous catalyst for
the synthesis of 2,4,6‐triphenylpyridine via cascade reac-
tions between dibenzyl ether and (E)‐1‐phenylethan‐1‐
one O‐acetyl oxime (Scheme 1). Different reaction
conditions were tested to maximize the yield of 2,4,6‐
NaHCO solution (3 x 5 ml). The ethyl acetate phase
3
was dehydrated utilizing anhydrous Na SO . The desired
2
4
product 2,4,6‐triphenylpyridine, was isolated by column
chromatography. The product identity was verified by
SCHEME 1 The synthesis of 2,4,6‐
triphenylpyridine via cascade reactions
utilizing VNU‐20 catalyst

NGUYEN ET AL.
3 of 11
triphenylpyridine (Table 1). Initially, the impact of tem-
perature on the yield of the desired product was explored
upgraded to 71% when the temperature was boosted to
120 °C. Increasing the temperature to 140 °C offered
91% yield of the expected product (Entry 5, Table 1). Next,
the influence of dibenzyl ether:(E)‐1‐phenylethan‐1‐one
O‐acetyl oxime molar ratio was studied (Entries 6–10,
Table 1). The reaction using 1 equivalent of (E)‐1‐
phenylethan‐1‐one O‐acetyl oxime afforded only 16%
(Entries 1–5, Table 1). The reaction was conducted in
chlorobenzene for 6 h, with reactant molar ratio of 1:4,
at 10 mol% catalyst, in the presence of 3 equivalents of
DTBP as oxidant. Only 4% yield was detected for the reac-
tion performed at 100 °C, and this value was considerably
a
TABLE 1 Screening of reaction conditions
b
Temperature
( C)
Reactant ratio
(mol:mol)
Catalyst
amount (mol%)
Oxidant
(equiv.)
o
c
Entry
Solvent
Yield
1
2
3
4
5
6
7
8
9
RT
1:4
1:4
1:4
1:4
1:4
1:1
1:2
1:3
1:4
1:5
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
DMSO
DMF
mesitylene
xylene
anisole
toluene
DCB
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
0
DTBP (3)
DTBP (3)
DTBP (3)
DTBP (3)
DTBP (3)
DTBP (3)
DTBP (3)
DTBP (3)
DTBP (3)
DTBP (3)
DTBP (3)
DTBP (3)
DTBP (3)
DTBP (3)
DTBP (3)
DTBP (3)
DTBP (3)
DTBP (3)
DTBP (3)
DTBP (3)
DTBP (3)
DTBP (3)
DTBP (3)
0
3
80
100
120
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
4
71
91
16
41
66
91
92
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
9
30
37
38
83
86
91
16
65
78
91
93
1
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
5
7
10
15
10
10
10
10
10
10
10
10
AgNO
3
8
(3)
(3)
K
2
S
2
O
2
aqTBHP (3)
dcTBHP (3)
DTBP (3)
DTBP (2)
DTBP (1)
DTBP (0)
56
58
91
91
77
12
a
Reaction conditions: Dibenzyl ether (0.10 mmol); solvent (1 ml); under argon; 6 h; PhCl: chlorobenzene; DMSO: dimethyl sulfoxide; DMF: N,N′‐
dimethylformamide; DCB: 1,2‐dichlorobenzene; DTBP: di‐tert‐butylperoxide; aqTBHP: tert‐butyl hydroperoxide in water; dcTBHP: tert‐butyl hydroperoxide
in decane.
b
dibenzyl ether:(E)‐1‐phenylethan‐1‐one O‐acetyl oxime molar ratio.
c
GC yield.

4
of 11
NGUYEN ET AL.
yield. As anticipated, extending the amount of the
ketoxime resulted in higher yield of the desired product.
Particularly, 41% and 66% yields were recorded in the
presence of 2 and 3 equivalents of the ketoxime, respec-
tively. The yield was improved to 91% for the case of 4
equivalents of the ketoxime (Entry 8, Table 1), while uti-
lizing more ketoxime did not enhance the yield
remarkably.
One important factor that must be considered is the
impact of catalyst concentration. The reaction was subse-
quently conducted in chlorobenzene for 6 h, with reac-
tant molar ratio of 1:4, using 3 equivalents of DTBP as
oxidant, in the presence of different amounts of VNU‐20
(Entries 19–23, Table 1). Only 16% yield of 2,4,6‐
triphenylpyridine was detected in the absence of the
VNU‐20, thus proving the significance of the iron‐organic
framework for the cascade transformations. The yield was
remarkably enhanced in the presence of the Fe‐MOF cat-
alyst, and 65% yield was recorded for the reaction utiliz-
ing 5 mol% catalyst. This value was enhanced to 78% for
the case of 7 mol% catalyst, while 91% yield was achieved
for the case of 10 mol% catalyst (Entry 22, Table 1). Utiliz-
ing more than 10 mol% catalyst did not improve the yield
Since the cascade reactions between dibenzyl ether
and (E)‐1‐phenylethan‐1‐one O‐acetyl oxime to produce
2
,4,6‐triphenylpyridine progressed with a solid catalyst,
the solvent would play a critical role due to the mass
transfer phenomenon. Previously, a variety of solvents
were employed for the synthesis of this heterocycles via
different methods, ranging from nonpolar solvents to
[8–10]
polar aprotic solvents.
In this work, the synthesis of
2
,4,6‐triphenylpyridine via cascade reactions was per-
formed in numerous solvents in the presence of the
VNU‐20 catalyst (Entries 11–18, Table 1). DMSO and
DMF were not suitable for this system, with very low
yields being detected. Noted that Ren et al. successfully
synthesized 2,4,6‐triphenylpyridines via a CuBr‐catalyzed
[
8]
coupling of ketomixes with aldehydes in DMSO .
Higher yields were observed for the experiments carried
out in mesitylene, xylene, and anisole, respectively. Tolu-
ene and dichlorobenzene displayed better performance,
affording the desired product in 83% and 86% yields,
respectively. Among these solvents, chlorobenzene was
the best candidate for this system, with 91% yield of
2
,4,6‐triphenylpyridine being obtained (Entry 18,
Table 1). Additionally, it should be mentioned that the
VNU‐20 was stable in chlorobenezene under the reaction
conditions.
FIGURE 2 Yields of 2,4,6‐triphenylpyridine vs heterogeneous
catalysts
FIGURE 1 Yields of 2,4,6‐triphenylpyridine vs homogeneous
FIGURE 3 Leaching experiment verified that no additional 2,4,6‐
catalysts
triphenylpyridine was generated after catalyst removal

NGUYEN ET AL.
5 of 11
of 2,4,6‐triphenylpyridine considerably. Similar to other
transformations progressed via C‐H bond activation, an
oxidant was required for the cascade reactions between
dibenzyl ether and (E)‐1‐phenylethan‐1‐one O‐acetyl
oxime. Several oxidants were consequently tested for the
system under standard conditions (Entries 24–28,
Table 1). Among several oxidants, di‐tert‐butylperoxide
should be used for the system, producing the expected
product in 91% yield (Entry 28, Table 1). Additionally, it
was possible to reduce the amount of the oxidant to 2
equivalents while the yield still remained 91% (Entry 29,
Table 1). Noted that only 12% yield of 2,4,6‐
triphenylpyridine was observed in the absence of di‐tert‐
butylperoxide, probably due to the air in the system.
To confirm the superiority of the VNU‐20 catalyst, a
variety of homogeneous and heterogeneous catalysts were
additionally utilized for the cascade reactions between
dibenzyl ether and (E)‐1‐phenylethan‐1‐one O‐acetyl
oxime to produce 2,4,6‐triphenylpyridine. The reaction
was performed at 140 °C in chlorobenzene for 6 h, with
reactant molar ratio of 1:4, using 3 equivalents of DTBP
as oxidant, in the presence of 10 mol% catalyst. In the first
experiment series, the activity of the VNU‐20 was com-
pared with that of common metal salts (Figure 1). The
FeCl ‐catalyzed transformation afforded 73% yield, while
2
5
2% yield was observed for the case of FeCl . Fe (NO )
3 3 3
exhibited similar activity to FeCl , with 57% yield being
3
noticed. The reaction utilizing Ni (NO ) catalyst also
3
2
progressed to 53% yield. Cu (OAc) and Co (NO ) were
2
3 2
less active, forming the desired product in 30% and 29%
yields, respectively. In the second experiment series, sev-
eral Fe‐MOFs and Cu‐MOFs were utilized as catalyst for
the transformation (Figure 2). Cu‐MOFs including Cu‐
MOF‐74, Cu (BDC) (DABCO), Cu (OBA) (BPY), and
2
2
2
2
Cu (BTC) expressed low activity for the reaction. The
3
2
reaction utilizing Fe O(BDC) catalyst progressed to 57%
3
3
yield, while 75% yield was detected for the case of
Fe O(BPDC) . Compared to these homogeneous and het-
FIGURE 4 Yields of 2,4,6‐triphenylpyridine in the presence of
3
3
TEMPO
erogeneous catalysts, the VNU‐20 displayed higher
SCHEME 2 Control experiments

6
of 11
NGUYEN ET AL.
efficiency, offering 91% yield of 2,4,6‐triphenylpyridine
under similar reaction conditions.
partially decomposed during the course of the experiment,
leaching phenomenon occurred, and consequently the
transformation did not proceed via strictly heterogeneous
catalysis. The reaction was performed at 140 °C in chloro-
benzene for 6 h, with reactant molar ratio of 1:4, using 2
equivalents of DTBP as oxidant, in the presence of
10 mol% catalyst. After the first 3 h with 39% yield of
2,4,6‐triphenylpyridine being recorded, the Fe‐MOF cata-
lyst was removed by centrifugation, and the liquid phase
was then transferred to a new and clean pressurized vial.
The vial was subsequently heated at 140 °C for additionally
Since the cascade reactions between dibenzyl ether and
(
E)‐1‐phenylethan‐1‐one O‐acetyl oxime utilizing the
VNU‐20 catalyst progressed in chlorobenzene phase, it
was demanded to confirm if soluble iron species contrib-
uted to the generation of 2,4,6‐triphenylpyridine via homo-
geneous catalysis. If the iron‐based framework was
3
h with magnetic stirring, and the yield of 2,4,6‐
triphenylpyridine was checked by GC analysis. Under
these conditions, no additional product was generated
after the Fe‐MOF catalyst removal (Figure 3). In a second
control experiment, the reaction utilizing 10 mol% VNU‐
20 catalyst was conducted under standard conditions for
6
hr. Upon completion of the transformation, the solid
catalyst was separation by centrifugation, and the amount
of leached iron in the filtrate, if any, was determined by
ICP‐OES. The concentration of iron in the filtrate was
8
ppm, corresponding to approximately 3% of iron (com-
pared to the total amount of iron in the VNU‐20 catalyst)
being soluble in the solution phase. These observations
supported that the cascade reactions between dibenzyl
FIGURE 5 Yields of 2,4,6‐triphenylpyridine in the presence of
pyridine
SCHEME 3 Plausible reaction pathway

NGUYEN ET AL.
7 of 11
ether and (E)‐1‐phenylethan‐1‐one O‐acetyl oxime to form
poison, in which the VNU‐20 was soaked in pyridine prior
to the catalytic transformation. Under these conditions,
the yield of 2,4,6‐triphenylpyridine was considerable influ-
enced by pyridine (Figure 5). This information supported
that Lewis acid sites on the iron‐based framework was cru-
cial for the cascade reactions.
2
,4,6‐triphenylpyridine utilizing the VNU‐20 catalyst
proceeded via strictly heterogeneous catalysis.
To attain more information for the cascade reactions
between dibenzyl ether and (E)‐1‐phenylethan‐1‐one
O‐acetyl oxime to produce 2,4,6‐triphenylpyridine
employing the VNU‐20 catalyst, some control experiments
were conducted. The reaction was performed at 140 °C in
chlorobenzene for 6 h, with reactant molar ratio of 1:4,
using 2 equivalents of DTBP as oxidant, in the presence
of 10 mol% catalyst. First, TEMPO (2,2,6,6‐tetrame-
thylpiperidine‐N‐oxyl) as antioxidant was introduced to
the reaction mixture at the beginning of the experiment.
Under this condition, only 12% yield of 2,4,6‐trip-
henylpyridine was observed after 6 hr (TEMPO test 1,
Figure 4). In the second experiment, after the first 3 h
reaction time, TEMPO was added, the resulting mixture
was then heated at 140 °C with magnetic stirring for addi-
tional 3 h, and the yield of 2,4,6‐triphenylpyridine was
checked by GC analysis. Similarly, the transformation
was remarkably affected by TEMPO (TEMPO test 2,
Figure 4). These results proposed that TEMPO interacted
with any radical species produced in the catalytic cycle,
leading to the termination of the transformation. Further-
more, the intermediate (Z)‐3‐amino‐1,3‐diphenylprop‐2‐
en‐1‐one (4) was detected by GC–MS for the reaction using
excess amount of dibenzyl ether (2) (Scheme 2a). In
another control experiment, the enaminone (4) and (E)‐
On the basis of these data and previous reports in the
literature, a plausible reaction pathway was proposed
(Scheme 3). The intermediate (A) was produced via an
initial single‐electron transfer (SET) mechanism in the
[
39–41]
presence of Fe (III) species and DTBP,
which was
oxidized by tert‐butyl peroxide radical to give the
oxonium species (B). Next, nucleophilic attack of a water
molecule to (B) produced the hemiacetal (C). The unsta-
ble intermediate (C) was consequently cleaved to give an
equimolar mixture of benzaldehyde (5) and benzyl alco-
hol (6), which were detected using GC–MS after the first
[
42]
30 minutes of reaction (Figure S8).
The in situ gener-
ated benzyl alcohol (6) was further oxidized to the corre-
sponding benzaldehyde (5) in the presence of Fe catalyst
and DTBP. Following this, the benzoyl radical species (D)
were produced from benzaldehyde (5) via a SET process
1‐(p‐tolyl)ethan‐1‐one O‐acetyl oxime (1a) were stirred in
chlorobenzene for 6 h utilizing VNU‐20 as catalyst under
argon atmosphere, and the product 2,4‐diphenyl‐6‐(p‐
tolyl)pyridine (3a) was produced in 37% yield (Scheme 2b).
Noted that the similar reaction conducted in the absence of
VNU‐20 offered the product (3a) in 32% isolated yield
(Scheme 2c), thus confirming negligible impact of iron
species on the cyclization steps. Additionally, the reaction
was performed in the presence of pyridine as a catalyst
FIGURE 7 FT‐IR analysis of the fresh (a) and reused (b) VNU‐20
FIGURE 6 Catalyst reuse studies
FIGURE 8 XRD analysis of the fresh (a) and reused (b) VNU‐20

8
of 11
NGUYEN ET AL.
a
TABLE 2 Synthesis of 2,4,6‐triphenylpyridines from ketoximes utilizing the VNU‐20 catalyst
b
Entry
Reactant 1
Reactant 2
Product
Yield (%)
1
85
78
70
75
82
55
78
86
2
3
4
5
6
7
8
(Continues)

NGUYEN ET AL.
9 of 11
TABLE 2 (Continued)
b
Entry
Reactant 1
Reactant 2
Product
Yield (%)
9
75
1
1
0
1
60
74
1
1
2
3
66
66
1
1
4
5
51
85
1
1
6
7
58
79
a
Reaction conditions: Dibenzyl ether (0.10 mmol) or benzylalcohol (0.10 mmol) or benzaldehyde (0.10 mmol) or (dimethoxymethyl)benzene (0.10 mmol);
ketoxime (0.4 mmol); DTBP (0.2 mmol); VNU‐20 (10 mol%); chlorobenzene (1 mL); 140 °C; under argon; 6 h.
b
Isolated yield.

10 of 11
NGUYEN ET AL.
[
10]
with Fe (III).
Simultaneously, the reductive cleavage of
1.160 g of (E)‐1‐phenylethan‐1‐one O‐acetyl oxime
afforded 0.736 g of 2,4,6‐triphenylpyridine (73.3% yield).
Ketoximes containing a substituent were also reactive
towards the cascade transformations, affording 4‐phe-
nyl‐2,6‐di‐p‐tolylpyridine (Entry 2, Table 2), 2,6‐bis(4‐
methoxyphenyl)‐4‐phenylpyridine (Entry 3, Table 2),
N‐O bond of ketoxime acetate (1) by Fe (II) species
offered the radical (E), which would be further reduced
by a Fe (II) species to give the Fe (III) imine anion com-
[
10,43]
plex (F).
Tautomerism of (F) afforded (G), which
reacted with the benzoyl radical (D) to give (H). Further
oxidation of (H) gave the enaminone (4) and Fe (II) spe-
cies back to the catalytic cycle, followed by condensation
of enaminone (4) with another ketoxime acetate species
1) to afford intermediate (I). Noted that the enaminone
4) could be formed by selective cross‐coupling between
2,6‐bis(4‐chlorophenyl)‐4‐phenylpyridine
(Entry
4,
Table 2), and 2,6‐bis(3‐chlorophenyl)‐4‐phenylpyridine
(Entry 5, Table 2) in 78%, 82%, 70%, and 75% yields,
respectively. (E)‐1‐(Thiophen‐2‐yl)ethan‐1‐one O‐acetyl
oxime was less reactive, though 4‐phenyl‐2,6‐di (thio-
phen‐2‐yl)pyridine was obtained in 55% yield (Entry 6,
Table 2). This could be explained based on the coordina-
tion of the sulfur atom in the ketoxime to iron species in
the framework, affecting the activity of the VNU‐20 cat-
alyst. Ren et al. previously synthesized 2,4,6‐tripheny-
lpyridines via a CuBr‐catalyzed coupling of ketomixes
(
(
[44]
radical species (D) and (E).
Finally, cyclization and
dehydration of intermediate (I) furnished the product (3).
As earlier noted, the VNU‐20 displayed higher effi-
ciency than many homogeneous and heterogeneous cata-
lysts. To furthermore underline significant aspects of the
VNU‐20 catalyst in the cascade reactions between
dibenzyl ether and (E)‐1‐phenylethan‐1‐one O‐acetyl
oxime to produce 2,4,6‐triphenylpyridine, its reusability
should be explored. The iron‐based framework was sub-
sequently studied for reutilization in 5 successive catalytic
runs. The reaction was performed at 140 °C in chloroben-
zene for 6 h, with reactant molar ratio of 1:4, using 2
equivalents of DTBP as oxidant, in the presence of
[
8]
with aldehydes . It was observed that the VNU‐20 cat-
alyst exhibited high activity in this transformation
(Entries 8–11, Table 2). Interestingly, we also found that
benzyl alcohol was reactive, producing the correspond-
ing 2,4,6‐triphenylpyridines in reasonable yields (Entries
12–14, Table 2). Nevertheless, lower yields of 2,4,6‐
triphenylpyridines suggested that the formation of ben-
zoyl radical from benzyl alcohol would be more difficult
than that from benzaldehyde and dibenzyl ether. Fur-
thermore, (dimethoxymethyl)benzene could be used as
an alternative starting material for the synthesis of
2,4,6‐triphenylpyridines under this protocol (Entries
15–17, Table 2).
1
0 mol% catalyst. After the experiment was complete,
the VNU‐20 was separated by centrifugation, washed
thoroughly with DMF and methanol, dried under vac-
uum on a Shlenkline at room temperature, and reused
for next experiment with similar reaction conditions. It
was noted that the VNU‐20 catalyst was reusable in the
synthesis of 2,4,6‐triphenylpyridine via the cascade reac-
th
tions. Certainly, in the 5 catalytic run, the transforma-
tion utilizing the recycled Fe‐MOF still afforded 91%
yield of 2,4,6‐triphenylpyridine (Figure 6). Additionally,
the recycled VNU‐20 was characterized by XRD
4 | CONCLUSIONS
Metal–organic framework VNU‐20 was utilized as a het-
erogeneous catalyst for the synthesis of 2,4,6‐
triphenylpyridines from ketoximes and dibenzyl ether via
cascade reactions. Additionally, benzyl alcohol and
(dimethoxymethyl)benzene were also reactive towards
the formation of 2,4,6‐triphenylpyridines in the presence
of this Fe‐MOF catalyst. The reaction was dramatically
controlled by the oxidant, and di‐tert‐butylperoxide
emerged as the most appropriate candidate. The VNU‐20
displayed higher efficiency than many homogeneous and
heterogeneous catalysts, accordingly highlighting signifi-
cant points of employing this iron‐based framework for
the transformation. Leaching studies proved that the for-
mation of 2,4,6‐triphenylpyridines via cascade reactions
utilizing the VNU‐20 catalyst proceeded via strictly hetero-
geneous catalysis. The iron‐based framework catalyst was
reusable in the synthesis of 2,4,6‐triphenylpyridines
without a noticeable deterioration in catalytic efficiency.
The transformation was not previously reported in the
(Figure 7) and FT‐IR (Figure 8), and the results were
compared with those of fresh catalyst sample. It was
noticed that structures of the Fe‐MOF were preserved
under the standard reaction conditions, though a slight
difference was observed.
Having these results in mind, we subsequently
expanded the research scope to the cascade reactions
between dibenzyl ether and different ketoximes utilizing
the VNU‐20 catalyst (Table 2). The reaction was per-
formed at 140 °C in chlorobenzene for 6 h, with reactant
molar ratio of 1:4, using 2 equivalents of DTBP as oxi-
dant, in the presence of 10 mol% catalyst. The desired
products were then isolated by using column chromatog-
raphy. Following this procedure, 2,4,6‐triphenylpyridine
was obtained in 85% yield via the cascade reactions
between dibenzyl ether and (E)‐1‐phenylethan‐1‐one O‐
acetyl oxime (Entry 1, Table 2). It was noted that gram‐
scale experiment utilizing 0.325 g of dibenzyl ether and

NGUYEN ET AL.
11 of 11
literature, and would offer alternative routes to triphe-
nylpyridines utilizing ketoximes as building blocks. More-
over, the advantages that these valuable heterocycles could
be produced using a recyclable catalyst would be beneficial
to the chemical industry.
[24] A. Herbst, C. Janiak, CrystEngComm 2017, 19, 4092.
[25] Q. Yang, Q. Xu, H.‐L. Jiang, Chem. Soc. Rev. 2017, 46, 4774.
[26] J. F. Kurisingal, R. Babu, S.‐H. Kim, Y. X. Li, J.‐S. Chang, S. J.
Cho, D.‐W. Park, Catal. Sci. Technol. 2018, 8, 591.
[27] S. M. J. Rogge, A. Bavykina, J. Hajek, H. Garcia, A. I. Olivos‐
Suarez, A. Sepúlveda‐Escribano, A. Vimont, G. Clet, P. Bazin,
F. Kapteijn, M. Daturi, E. V. Ramos‐Fernandez, F. X. L.i.
Xamena, V. V. Speybroeck, J. Gascon, Chem. Soc. Rev. 2017,
ORCID
4
6, 3134.
28] A. Dhakshinamoorthy, A. M. Asiri, H. Garcia, Chem. Commun.
017, 53, 10851.
Thach N. Tu https://orcid.org/0000-0003-4240-0224
Nam T.S. Phan https://orcid.org/0000-0002-5928-7638
[
[
[
2
29] S. Yuan, J.‐S. Qin, L. Zou, Y.‐P. Chen, X. Wang, Q. Zhang, H.‐
C. Zhou, J. Am. Chem. Soc. 2016, 138, 6636.
REFERENCES
30] K. C. Jayachandrababu, D. S. Sholl, S. Nair, J. Am. Chem. Soc.
[
1] B. Rao, C. C. Chong, R. Kinjo, J. Am. Chem. Soc. 2018, 140, 652.
2] C. Patel, M. Mohnike, M. C. Hilton, A. McNally, Org. Lett. 2018,
2017, 139, 5906.
[
[
[
[
31] D.‐M. Chen, J.‐Y. Tian, C.‐S. Liu, Inorg. Chem. 2016, 55, 8892.
2
0, 2607.
3] Y. Yan, H. Li, Z. Li, B. Niu, M. Shi, Y. Liu, J. Org. Chem. 2017,
2, 8628.
32] J. Tang, J. Wang, Environ. Sci. Technol. 2018, 52, 5367.
[
33] G. Lan, K. Ni, Z. Xu, S. S. Veroneau, Y. Song, W. Lin, J. Am.
Chem. Soc. 2018, 140, 5670.
8
[
[
4] F. Yang, J. Yu, Y. Liu, J. Zhu, J. Org. Chem. 2017, 82, 9978.
5] W. W. Tan, Y. J. Ong, N. Yoshikai, Angew. Chem. Int. Ed. 2017,
[
[
34] Y. Georgiou, J. A. Perman, A. B. Bourlinos, Y. Deligiannakis,
J. Phys. Chem. C 2018, 122, 4859.
5
6, 8240.
35] M. Pu, Y. Ma, J. Wan, Y. Wang, J. Wang, M. L. Brusseau, Catal.
Sci. Technol. 2017, 7, 1129.
[
6] J.‐C. Xiang, M. Wang, Y. Cheng, A.‐X. Wu, Org. Lett. 2016, 18, 24.
[
7] X. Zhang, Z. Wang, K. Xu, Y. Feng, W. Zhao, X. Xu, Y. Yan, W.
[
36] E. Rahmani, M. Rahmani, Ind. Eng. Chem. Res. 2018, 57, 169.
Yi, Green Chem. 2016, 18, 2313.
[
37] D. Julião, A. D. S. Barbosa, A. F. Peixoto, C. Freire, B. D. Cas-
[
8] Z.‐H. Ren, Z.‐Y. Zhang, B.‐Q. Yang, Y.‐Y. Wang, Z.‐H. Guan,
Org. Lett. 2011, 13, 5394.
tro, S. S. Balula, L. Cunha‐Silva, CrystEngComm 2017, 19, 4219.
[
38] P. H. Pham, S. H. Doan, H. T. T. Tran, N. N. Nguyen, A. N. Q.
[
9] M.‐N. Zhao, Z.‐H. Ren, L. Yu, Y.‐Y. Wang, Z.‐H. Guan, Org.
Lett. 2016, 18, 1194.
Phan, H. V. Le, T. N. Tu, N. T. S. Phan, Catal. Sci. Technol.
2018) In press, 8, 1267. https://doi.org/10.1039/C7CY02139A
[
10] Y. Yi, M.‐N. Zhao, Z.‐H. Ren, Y.‐Y. Wang, Z.‐H. Guan, Green
Chem. 2017, 19, 1023.
[
[
[
39] J. Feng, G. Lu, M. Lv, C. Cai, Synlett 2015, 26, 915.
40] J. Feng, M. F. Lv, G. P. Lu, C. Cai, Org. Chem. Front. 2015, 2, 60.
[
11] Y. Mu, X. Tan, Y. Zhang, X. Jing, Z. Shi, Org. Chem. Front.
41] J. Feng, M. F. Lv, G. P. Lu, C. Cai, Org. Biomol. Chem. 2015,
2
016, 3, 380.
13, 677.
[
12] S. Kaur, M. Kumar, V. Bhalla, Chem. Commun. 2015, 51, 4085.
[
[
[
42] N. Khatun, A. Banerjee, S. K. Santra, W. Ali, B. K. Patel, RSC
[
13] G. Raju, V. Guguloth, B. Satyanarayana, RSC Adv. 2016, 6,
Adv. 2015, 5, 36461.
4
5036.
43] Y. Fu, P. Wang, X. Guo, P. Wu, X. Meng, B. Chen, J. Org. Chem.
[
[
[
[
[
[
14] X. Tang, L. Huang, Y. Xu, J. Yang, W. Wu, H. Jiang, Angew.
2016, 81, 11671.
Chem. Int. Ed. 2014, 53, 4205.
44] Z. Zhu, X. Tang, J. Li, X. Li, W. Wu, G. Deng, H. Jiang, Chem.
Commun. 2017, 53, 3228.
15] Y. Gao, J. Liu, Z. Li, T. Guo, S. Xu, H. Zhu, F. Wei, S. Chen, H.
Gebru, K. Guo, J. Org. Chem. 2018, 83, 2040.
16] L. R. Mingabudinova, V. V. Vinogradov, V. A. Milichko, E. Hey‐
Hawkins, A. V. Vinogradov, Chem. Soc. Rev. 2016, 45, 5408.
SUPPORTING INFORMATION
17] L. Wang, X.‐Y. Liang, Z.‐Y. Chang, L.‐S. Ding, S. Zhang, B.‐J.
Li, ACS Appl. Mater. Interfaces 2018, 10, 42.
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
18] A. C. Elder, S. Bhattacharyya, S. Nair, T. M. Orlando, J. Phys.
Chem. C 2018, 122, 10413.
19] C.‐W. Kung, K. Otake, C. T. Buru, S. Goswami, Y. Cui, J. T.
Hupp, A. M. Spokoyny, O. K. Farha, J. Am. Chem. Soc. 2018,
1
40, 3871.
20] N. Li, J. Xu, R. Feng, T.‐L. Hu, X.‐H. Bu, Chem. Commun. 2016,
2, 8501.
How to cite this article: Nguyen VHH, Doan
SH, Van TT, et al. A new route to
triphenylpyridines utilizing ketoximes as building
blocks via cascade reactions under iron‐organic
framework catalysis. Appl Organometal Chem.
[
[
5
21] K. D. Nguyen, C. Kutzscher, F. Drache, I. Senkovska, S. Kaskel,
Inorg. Chem. 2018, 57, 1483.
[
22] Y.‐X. Tan, F. Wang, J. Zhang, Chem. Soc. Rev. 2018, 47, 2130.
23] Z. Hu, D. Zhao, CrystEngComm 2017, 19, 4066.
2019;e4841. https://doi.org/10.1002/aoc.4841
[