Iron-catalyzed one-pot sequential transformations: Synthesis of quinazolinones via oxidative Csp3–H bond activation using a new metal-organic framework as catalyst

Article abstract of DOI:10.1016/j.jcat.2018.11.031

A new mixed-linker iron-based MOF VNU-21 [Fe₃(BTC)(EDB)₂·12.27H₂O] was synthesized via mixed-linker synthetic strategy using 1,3,5-benzenetricarboxylic acid, 4,4′-ethynylenedibenzoic acid, and FeCl₂. The VNU-21 was consequently used as a recyclable heterogeneous catalyst in the one-pot synthesis of quinazolinones via two steps under oxygen atmosphere. The synthetic scheme involved iron-catalyzed oxidative Csp³–H bond activation to achieve decarboxylation of phenylacetic acids, and succeeding metal-free oxidative cyclization with 2-aminobenzamides. The VNU-21 was more effective than a series of heterogeneous and homogeneous catalysts. It was possible to reutilize the iron-based framework without a considerable deterioration in catalytic performance. To our best knowledge, this one-pot synthesis of quinazolinones was not previously performed using a recyclable catalyst.

Full text of DOI:10.1016/j.jcat.2018.11.031

Journal of Catalysis 370 (2019) 11–20
Contents lists available at ScienceDirect
Journal of Catalysis
journal homepage: www.elsevier.com/locate/jcat
Iron-catalyzed one-pot sequential transformations: Synthesis of
quinazolinones via oxidative Csp3AH bond activation using a new
metal-organic framework as catalyst
Tuong A. To a,1, Yen H. Vo a,1, Hue T.T. Nguyen b, Phuong T.M. Ha a, Son H. Doan a, Tan L.H. Doan b,
Shuang Li c, Ha V. Le a,c, Thach N. Tu b, , Nam T.S. Phan a,
⇑
⇑
a Faculty of Chemical Engineering, HCMC University of Technology, VNU-HCM, 268 Ly Thuong Kiet, District 10, Ho Chi Minh City, Viet Nam
b Center for Innovative Materials and Architectures, VNU-HCM, Quarter 6, Linh Trung Ward, Thu Duc District, Ho Chi Minh City, Viet Nam
c Institute of ChemistryꢀFunctional Materials, Technische Universität Berlin, BA2, Hardenbergstraße 40, 10623 Berlin, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A new mixed-linker iron-based MOF VNU-21 [Fe3(BTC)(EDB)2ꢁ12.27H2O] was synthesized via mixed-
linker synthetic strategy using 1,3,5-benzenetricarboxylic acid, 4,40-ethynylenedibenzoic acid, and
FeCl2. The VNU-21 was consequently used as a recyclable heterogeneous catalyst in the one-pot synthesis
of quinazolinones via two steps under oxygen atmosphere. The synthetic scheme involved iron-catalyzed
oxidative Csp3AH bond activation to achieve decarboxylation of phenylacetic acids, and succeeding
metal-free oxidative cyclization with 2-aminobenzamides. The VNU-21 was more effective than a series
of heterogeneous and homogeneous catalysts. It was possible to reutilize the iron-based framework with-
out a considerable deterioration in catalytic performance. To our best knowledge, this one-pot synthesis
of quinazolinones was not previously performed using a recyclable catalyst.
Received 14 April 2018
Revised 20 November 2018
Accepted 23 November 2018
Keywords:
Iron-organic framework
Quinazolinones
Tandem
Csp3AH bond
Catalysis
Ó 2018 Elsevier Inc. All rights reserved.
1. Introduction
benzaldehydes, benzyl alcohols, or benzylic hydrocarbons [13].
Yin
and
co-workers
achieved
quinazolinones
from
Quinazolinones and their derivatives are a well-known class of
nitrogen-containing heterocycles, existing in numerous products
with significant biological activities [1–3]. A variety of synthetic
protocols towards these valuable heterocyclic scaffolds have been
explored [4,5]. The synthesis of organic compounds via one-pot
multi-step procedures has been considered as an effective and
environmetally benign approach, since the isolation of intermedi-
ate products is not required, thus minimizing toxic waste and sim-
plifying practical issues [6,7]. López and co-workers previously
prepared quinazolinones from 2-nitrobenzamides and aryl aldehy-
des via a one-pot process [8]. Quinazolinones were also achieved
from 2-aminobenzamides and alcohols via one-pot transforma-
tions utilizing and FeCl3 [9], ruthenium complex [10], and iridium
complex [11] as catalysts. Hu and co-workers obtained quinazoli-
nones via the same reaction with Fe(NO3)3/TEMPO catalyst system
[12]. Upadhyaya and co-workers reported a one-pot CuI-catalyzed
synthesis of quinazolinones from 2-bromobenzamides and
2-aminobenzamides and phenylacetic acids via one-pot FeCl3-
catalyzed oxidative functionalization of sp3 C-H bonds, decarboxy-
lation, and subsequent cyclization [14]. To develop greener
protocols for the synthesis of quinazolinones, heterogeneous cata-
lysts with advantages of recyclability and reusability should be
explored.
The discovery of metal-organic frameworks (MOFs), a new class
of crystalline hybrid porous materials, has been considered as one
breakthrough in chemistry during the last two decades [15,16].
Integrating interesting properties of both metal nodes and organic
linkers, these frameworks have been recognized as potential candi-
dates for a variety of applications, extending from gas capture and
storage to catalysis [17–20]. Furthermore, MOFs have been
explored to reduce the difference between heterogeneous and
homogeneous catalysts owing to their unique features. Among a
long series of well-known MOFs, iron-organic frameworks have
attracted considerable attention [21–29]. Nevertheless, these
MOFs are generally constructed from oxo-centered trimmers of
octahedral Fe(III) SBUs [21,22,30–32], and indeed, MOFs composed
of Fe(II)-based SBUs have been limited in the literature [27,33–35].
In this work, we wish to report the synthesis of a new iron-based
MOF, termed VNU-21 (where VNU = Vietnam National University).
⇑
Corresponding authors.
E-mail addresses: tnthach@inomar.edu.vn (T.N. Tu), ptsnam@hcmut.edu.vn
(N.T.S. Phan).
1
These authors contributed equally to this work.
https://doi.org/10.1016/j.jcat.2018.11.031
0021-9517/Ó 2018 Elsevier Inc. All rights reserved.

12
T.A. To et al. / Journal of Catalysis 370 (2019) 11–20
Single crystal analysis revealed that this MOF, formulated as
Fe3(BTC)(EDB)2ꢁ12.27H2O
(BTC3ꢀ = 1,3,5-benzenetricarboxylate;
EDB2ꢀ = 4,40-ethynylenedibenzoate), constructed from mixed-
linkers of BTC3ꢀ EDB2ꢀ and infinite [Fe3(CO2)7]1 rod SBU.
Furthermore, the VNU-21 was utilized as a recyclable catalyst in
the one-pot synthesis of quinazolinones, including iron-catalyzed
oxidative Csp3AH bond activation to achieve decarboxylation of
phenylacetic acids, and succeeding metal-free oxidative cyclization
with 2-aminobenzamides.
the orthorhombic space group, Pbcn (No. 60), with unit cell param-
eters, a = 25.26917, b = 33.43879, and c = 13.62934 Å. Indeed, the
VNU-21 was identified to possess the same topology with the
VNU-20 [36]; however, with the larger pore dimension. Particu-
larly, this material was built from H3BTC and H2EDB linkers
(Fig. 1a) and the sinusoidal [Fe3(CO2)7]1 iron-rod SBU [37,38]
(Fig. 1b), which was constructed from three distinct octahedral
iron centers in consecutive order. The iron centers then connected
each other through the sharing edge and vertex to infinite Fe-rod
SBU (Fig. 1b). The sinusoidal [Fe3(CO2)7]1 iron-rod metal cluster
was finally joined by the horizontal BTC3ꢀ linker (Fig. 1e) and the
vertical EDB2ꢀ linker (Fig. 1f) to form the 3-dimensional architec-
ture of the VNU-21 (Fig. 1c, d). It should be noted that the VNU-
21 possessed open rectangular window of 8.9 ꢂ 12.6 Å2 with thick
,
2. Experimental
2.1. Synthesis of metal-organic framework VNU-21
The mixture of H2EDB (0.12 g, 0.45 mmol), H3BTC (0.021 g,
0.1 mmol), and FeCl2 (0.12 g, 0.94 mmol) was added to DMF
(12 mL), and sonicated for 5 min to afford a clear solution. Subse-
quently, this solution was divided into glass tubes, which were
sealed and placed in an isothermal oven, pre-heated at 175 °C,
for 72 h, to achieve reddish rhombic prism shape crystals of
VNU-21. Consequently, the VNU-21 crystals were exchanged by
DMF (5 ꢂ 15 mL), and methanol (5 ꢂ 15 mL). The VNU-21 crystals
were then exchanged by liquid CO2, evacuated under CO2 super-
critical condition, and activated under dynamic vacuum at room
temperature to obtain dried VNU-21 (0.068 g, 75% yield based on
H3BTC). Elemental analysis: Fe3C41H43.54O26.27 = Fe3(BTC)(EDB)2-
ꢁ12.27H2O (Cal: %C = 43.77; %H = 3.87; %N = 0. Found: %C = 43.23;
%H = 3.33; %N = 0.26).
walls architecture, constructed of infinite rings to rings
action of EDB2ꢀ linkers (Fig. 1c, f).
p-p inter-
Furthermore, PXRD analysis of the as-synthesized and simu-
lated samples confirmed the bulk phase purity of the obtained
VNU-21 (Fig. S1). The VNU-21 was consequently exchanged and
activated under CO2 supercritical condition, for which, the struc-
tural maintenance after the activation step was verified by PXRD
analysis (Fig. S1). Elemental microanalysis (EA) additionally con-
firmed the chemical formula of the VNU-21 as Fe3(BTC)(EDB)2-
ꢁ12.27H2O (Cal: %C = 43.77; %H = 3.87; %N = 0. Found: %C = 43.23;
%H = 3.33; %N = 0.26). Fourier transform-infrared (FT-IR) spec-
troscopy analysis indicated the existence of the bands centering
at 1610 cmꢀ1, which was assigned to vC=O stretch vibration of
coordinated carboxylate species in the framework (Fig. S2). The
thermal stability of the VNU-21 was investigated by thermogravi-
metric analysis (TGA). Indeed, TGA result displayed less than 2%
weight loss in the range from ambient temperature to 200 °C,
and the residual metal oxides, ascribed to Fe2O3, in good agree-
ment with those from model formula (Fig. S3). The permanent
porosity of VNU-21 was explored via nitrogen adsorption at 77 K
with BET surface areas of 1440 m2 gꢀ1 being recorded (Fig. S4). Cer-
tainly, this number was consistent with the simulated surface
areas calculated by utilizing Material Studio 6.0 software
(1419 m2 gꢀ1). Furthermore, the deconvoluted X-ray photoelectron
spectrum (XPS) of the Fe 2p3/2 region for the VNU-21 showed the
peaks attributed to Fe(II) and Fe(III) ions, which are located at
709.5 and 711 eV, respectively (Fig. S5) [35,36]. This result indi-
cated that iron species with the mixed oxidation state are present
in the VNU-21 framework.
2.2. Catalytic studies
In
a typical experiment, a solution of phenylacetic acid
(0.3 mmol, 40.8 mg) in DMF (0.5 mL) was added to a 10 mL vial
with the VNU-21 catalyst (5.5 mg, 5 mol%). The mixture was stir-
red at 120 °C for 4 h under an oxygen atmosphere. After that, the
catalyst was removed by filtration.
A
solution of 2-
aminobenzamide (0.2 mmol, 27.2 mg) in DMSO (0.5 mL) was then
added to the reactor. The mixture was additionally stirred at 120 °C
for 5 h under oxygen. The GC yield of benzaldehyde and 2-
phenylquinazolin-2(3H)-one were monitored by withdrawing
samples from the reaction mixture, quenching with brine (1 mL),
extracting with ethyl acetate (3 ꢂ 1 mL), drying over anhydrous
Na2SO4, and analyzing by GC regarding diphenyl ether as internal
standard. After the completion of the second step, the reaction
mixture was cooled to room temperature. Resulting solution was
quenched with brine (5 mL), extracted by ethyl acetate
(3 ꢂ 5 mL), dried over anhydrous Na2SO4 prior to the removal of
solvent under vacuum. The crude product was purified by silica
gel column chromatography using hexane and ethyl acetate (1:1,
v/v) as eluent. The structure of 2-phenylquinazolin-4(3H)-one
was verified by GC–MS, 1H NMR and 13C NMR. For the leaching
test, after the first 4 h reaction time, the catalyst was removed by
filtration. The solution phase was transferred to a new and clean
reactor. New phenylacetic acid was added, and the resulting mix-
ture was subsequently stirred for additional 4 h at 120 °C under
an oxygen atmosphere. The yield of benzaldehyde was monitored
by GC.
3.2. Catalytic studies
The VNU-21 was utilized as a heterogeneous catalyst for the
one-pot synthesis of 2-phenylquinazolin-4(3H)-one, including
iron-catalyzed oxidative Csp3AH bond activation of phenylacetic
acid (step 1, Scheme 1), and subsequent oxidative cyclization with
2-aminobenzamide (step 2, Scheme 1). Chen and co-workers previ-
ously performed this one-pot transformation to achieve quinazoli-
nones in the presence of FeCl3 catalyst for 12 h [14]. As the second
step proceeded in the absence of the iron-based catalyst, it was
decided to separate the VNU-21 after the first step to increase
the catalyst lifetime. Preliminary results also indicated that the
yield of 2-phenylquinazolin-4(3H)-one was considerably improved
if DMSO was utilized as a co-solvent in the second step. Reaction
conditions were screened to maximize the yield of the quinazoli-
none (Table 1). The first step was conducted using 0.22 mmol
phenylacetic acid in 0.5 mL solvent 1 at 120 °C for 3 h under an
oxygen atmosphere, with 0.01 mmol VNU-21 catalyst. After that,
the catalyst was removed, 0.20 mmol 2-aminobenzamide in
0.5 mL solvent 2 was added, and the resulting mixture was heated
at 120 °C for 5 h under an oxygen atmosphere. Initially, the impact
of solvent in the first step was explored (Entries 1–8, Table 1). It
3. Results and discussion
3.1. Synthesis and characterization of VNU-21
The iron-based MOF VNU-21 was synthesized in 75% yield via
mixed-linker synthetic strategy using 1,3,5-benzenetricarboxylic
acid, 4,40-ethynylenedibenzoic acid, and FeCl2. Single crystal X-
rays diffraction results indicated that the VNU-21 crystallized in

T.A. To et al. / Journal of Catalysis 370 (2019) 11–20
13
Fig 1. The crystal structure of VNU-21 was assembled from sinusoidal rod [Fe3(CO2)7]1 (b) that are stitched horizontally by BTC3ꢀ and vertically by EDB2ꢀ (a, e and f) to form
the red crystals (d) with structure highlighted by a rectangular window of 8.9 ꢂ 12.6 Å2 (c). Atom colors: Fe, blue, light blue and orange polyhedra; C, black; O, red. All H
atoms are omitted for clarity. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Increasing the amount of phenylacetic acid to 1.5 equivalents, the
yield of 2-phenylquinazolin-4(3H)-one was improved to 67%
(Entry 12, Table 1). One more factor that must be explored is the
amount of the VNU-21 catalyst (Entries 15–18, Table 1). Noted that
only 3% yield was recorded in the absence of the catalyst, thus ver-
ifying the requirement of the iron-organic framework for the trans-
formation (Entry 15, Table 1). The yield was considerably improved
in the presence of the framework catalyst, affording 67% for the
reaction utilizing 3.3 mol% catalyst (Entry 16, Table 1). In was
noticed that by increasing the reaction of the first step to 4 h, the
yield of 2-phenylquinazolin-4(3H)-one was remarkably upgraded
Scheme 1. Synthesis of 2-phenylquinazolin-4(3H)-one via one-pot two-step.
to 89% in the presence of 3.3 mol% catalyst (Entry 19, Table 1).
The influence of solvent in the second step on the yield of 2-
phenylquinazolin-4(3H)-one was also studied (Entries 19–25,
was observed that the first step of the transformation was favored
in DMF as solvent, affording 2-phenylquinazolin-4(3H)-one in 36%
yield (Entry 1, Table 1). DMA exhibited similar performance with
31% yield being detected, while NMP, chlorobenzene, dichloroben-
zene, p-xylene, diglyme, and diethyl carbonate should not be used
(Entries 2–8, Table 1).
Having these results, we consequently investigated the impact
of phenyl acetic acid: 2-aminobenzamide molar ratio on the yield
of 2-phenylquinazolin-4(3H)-one (Entries 9–13, Table 1). Experi-
mental results indicated that the reaction was favored by excess
amounts of phenylacetic acid. The reaction afforded 34% yield
when 1 equivalent of phenylacetic acid was used (Entry 9, Table 1).
Table 1). It was noted that DMSO was the solvent of choice for
the second step (Entry 19, Table 1). Other solvents, including
DMF, chlorobenzene, dichloroethane, diethyl carbonate, dioxane,
and tert-butanol exhibited low performance for the transformation
(Entries 20–25, Table 1).
Since the one-pot synthesis of 2-phenylquinazolin-4(3H)-one
from phenylacetic acid and 2-aminobenzamide utilizing the
VNU-21 catalyst was conducted in liquid phase, an essential aspect
that should be studied is the leaching of iron species from the
framework to the solution. Control experiments were conse-
quently performed to verify if the transformation proceeded via
truly heterogeneous catalysis or not. Noted that the first step

14
T.A. To et al. / Journal of Catalysis 370 (2019) 11–20
Table 1
Screening reaction conditions to maximize yield of 2-phenylquinazolin-4(3H)-one.a
Entry
Solvent 1 (0.5 mL)
Reactant 1 (mmol)
Catalyst (mmol)
Temperature (°C)
Reactant 2 (mmol)
Solvent 2 (0.5 mL)
Yield (%)
1
2
3
4
5
6
7
8
DMF
DMA
NMP
Chlorobenzene
DCB
p-xylene
Diglyme
DEC
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.20
0.22
0.25
0.30
0.60
0.30
0.30
0.30
0.30
0.30
0.30
0.30
0.30
0.30
0.30
0.30
0.30
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0
0.005
0.01
0.015
0.02
0.01
0.01
0.01
0.01
0.01
0.01
0.01
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
36
31
3
18
12
5
8
5
9
34
36
40
67
70
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
42
67
69
72
89b
16b
41b
5b
DMF
DMF
DMF
DMF
chlorobenzene
DCE
DEC
dioxane
tert-butanol
25b
8b
DMF
14b
a
The first step was conducted for 3 h under an oxygen atmosphere; the second step was conducted for 5 h under an oxygen atmosphere; DMF: N,N0-dimethylformamide;
DMA: Dimethylacetamide; DMSO: Dimethyl sulfoxide; NMP: N-Methyl-2-pyrrolidone; DCB: dichlorobenzene; DEC: diethyl carbonate; DCE:dichloroethane.
b
The first step was conducted for 4 h under an oxygen atmosphere. GC yield of 2-phenylquinazolin-4(3H)-one.
involved iron-catalyzed oxidative Csp3AH bond activation of
phenylacetic acid to produce benzaldehyde (step 1, Scheme 1),
while the oxidative cyclization of benzaldehyde with 2-
aminobenzamide (step 2, Scheme 1) proceeded under metal-free
conditions. We consequently explored the contribution of soluble
iron species, if any, to the formation of benzaldehyde in the first
step. The first step was conducted using 0.3 mmol phenylacetic
acid in 0.5 mL DMF at 120 °C for 4 h under an oxygen atmosphere,
with 0.01 mmol VNU-21 catalyst. After the experiment, the VNU-
21 catalyst was separated from the mixture. The liquid phase
was transferred to a second reactor, and fresh phenylacetic acid
was subsequently added to the reactor. The resulting mixture
was heated at 120 °C for 4 h under an oxygen atmosphere. Yield
of benzaldehyde was monitored by GC. It was noticed that almost
no additional benzaldehyde was generated under these conditions
(Leaching test 1, Fig. 2). In a second experiment, after the first
90 min reaction time with 40% yield of benzaldehyde being
detected, the VNU-21 catalyst was isolated by centrifugation. The
DMF solution was transferred to a second reactor, and the mixture
was heated at 120 °C for further 150 min. Similar to the first leach-
ing experiment, no additional benzaldehyde was recorded after the
catalyst removal (Leaching test 2, Fig. 2). Moreover, ICP analyses of
the fresh and spent catalysts were carried out, indicating that the
amount of iron in the VNU-21 remained unchanged during the
experiment (16% wt/wt). Additionally, ICP analysis of the filtrate
showed that less than 1% of iron (compared to the total amount
of iron in the catalyst) was soluble in the solution. These data
would verify that the oxidative Csp3AH bond activation of
phenylacetic acid to produce benzaldehyde (step 1, Scheme 1) only
proceeded in the presence of the solid VNU-21 catallyst.
To emphasize the positive aspects of utilizing the VNU-21 as
catalyst for the one-pot synthesis of 2-phenylquinazolin-4(3H)-
one from phenylacetic acid and 2-aminobenzamide, a series of
heterogeneous and homogeneous catalysts were also tested for
this transformation. The first step was conducted using 0.22 mmol
phenylacetic acid in 0.5 mL DMF at 120 °C for 4 h under an oxygen
atmosphere, with 0.01 mmol catalyst. After that, the solid catalyst
was removed, 0.20 mmol 2-aminobenzamide in 0.5 mL DMSO was
added, and the resulting mixture was heated at 120 °C for 5 h
under an oxygen atmosphere. The reaction using FeCl3 proceeded
to 67% yield of 2-phenylquinazolin-4(3H)-one, while 33% yield
was obtained for the case of FeSO4. This observation suggested that
both Fe(II) and Fe(III) species were active for the transformation.
Indeed, it was previously reported that both Fe(II) and Fe(III) cata-
lysts could be used for similar transformations [14,39-41]. Fe3O
(BDC)3 [BDC = 1,4-benzenedicarboxylate] was more active towards
the reaction, affording 72% yield. Fe3O(BPDC)3 [BPDC = 4,40-biphe
nyldicarboxylate] was noticed to exhibit higher activity, with 85%
yield of 2-phenylquinazolin-4(3H)-one being achieved. MOFs con-
taining other metals were less active than Fe-MOFs in the oxidative
Csp3AH bond activation of phenylacetic acid, producing the
desired quinazolinone product in lower yields. The reaction using
Cu2(OBA)2(BPY)
bipyridine] catalyst afforded 46% yield, while only 12% yield was
[OBA = 4,40-oxybis(benzoate);
BPY = 4,40-
Fig. 2. Leaching test showed that the first step did not proceed in the absence of the
VNU-21.

T.A. To et al. / Journal of Catalysis 370 (2019) 11–20
15
noticed for that utilizing Cu-MOF-199 as catalyst. Zr-MOF-808 was
almost inactive for the reaction, affording only 3% yield. Similarly,
the reaction utilizing Co-ZIF-67 catalyst progressed with difficulty,
with only 2% yield being detected. It should be noted that FeBTC
[BTC = 1,3,5-benzenetricarboxylate], the Fe-MOF prepared using
1,3,5-benzenetricarboxylic acid linker, exhibited low activity for
the transformation, affording only 10% yield. The low catalytic
activity of the FeBTC can be attributed to the low activity of the
iron trimesic cluster comparing with the rod-based iron cluster
in the VNU-21. Additionally, VNU-20, the mixed linker Fe-MOF
synthesized from 1,3,5-benzenetricarboxylic acid and 2,6-
napthalenedicarboxylic acid, was used. The VNU-21 possessed
the same topology with the VNU-20 [36], however with the larger
pore dimension (8.9 ꢂ 12.6 Å2 vs 6.0 ꢂ 8.7 Å2). Under these condi-
tions, the VNU-20 was less active than the VNU-21, offering 78%
yield. Compared to these catalysts, the VNU-21 displayed the best
performance, with 89% yield being achieved (Fig. 3).
To gain insight into the reaction pathway, several control exper-
iments were carried out (Scheme 2). First, the yield of benzalde-
hyde (2) in the first step was significantly decreased in the
presence of (2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO) as a
radical scavenger (Scheme 2a). This result verified that the oxida-
tive decarboxylation of phenylacetic acid (1) progressed via a rad-
ical pathway. In the next two experiments, we tried to determine
intermediates of this process (Scheme 2b and 2c). High yields of
2 were obtained when mandelic acid (A) and benzoylformic acid
(B) (in the absence of VNU-21) were employed as reactant in the
first step of our protocol, suggesting that these two acids could
be the intermediates. The second step pathway was also investi-
gated by the next two experiments (Scheme 2d and e). 2-
Phenylquinazolin-4(3H)-one (4) was produced in excellent yield
when 2-aminobenzamide (3) and benzaldehyde (2) was employed
(Scheme 2d), while the yield declined to 59% when molecular sieve
was added (Scheme 2e). Therefore, water could play a vital role on
this step. On the basis of these results and previous reports in the
literature [14,42],
(Scheme 3).
a
plausible mechanism was proposed
Fig. 3. Yield of 2-phenylquinazolin-4(3H)-one vs different catalysts.
Scheme 2. Control experiments.

16
T.A. To et al. / Journal of Catalysis 370 (2019) 11–20
Scheme 3. Proposed reaction pathway.
Under VNU-21 catalysis,
formed by aerobic oxidation via radical pathway following by
dehydrogenation to afford -ketoacid B. Aromatic aldehyde 2
a
-hydroxycarboxylic acid
A
was
and the resulting mixture was heated at 120 °C for 5 h under an
oxygen atmosphere. The recovered framework was then washed
thoroughly with DMF, and methanol to get rid of any physisorbed
materials, and consequently activated under vacuum at ambient
temperature on a Shlenk line for 1 h. New catalytic experiment
was thereafter carried out using the recovered catalyst under the
same conditions. Experimental data indicated that it was possible
to reuse the VNU-21 catalyst for the one-pot synthesis of 2-
phenylquinazolin-4(3H)-one from phenylacetic acid and 2-
aminobenzamide without a noticeable deterioration in catalytic
efficiency. Certainly, 88% yield of 2-phenylquinazolin-4(3H)-one
was obtained in the 5th run (Fig. 4). The FT-IR analysis results of
both fresh reutilized VNU-21 samples displayed similar absorption
characteristics (Fig. 5). Additionally, the XRD result of the reuti-
lized catalyst suggested that the iron-based framework maintained
a
was then produced by decarboxylation of B [14]. After the first
step, 3 was added to the reaction and reacted with 2 to obtain
imine C. Intermediate E was generated by a 6-endo-trig cyclization
of C. The presence of water in the reaction media could accelerate
the cyclization through intermediate D which was produced by
nucleophilic addition of water to C. 6-Exo-tet cyclization of D sub-
sequently occurred, creating intermediate E. Finally, product 4 was
formed by oxidative dehydrogenation of E in the presence of oxy-
gen (Scheme 3) [42]. From experimental point of view, it should be
noted that performing the catalyst-free cyclization of benzalde-
hyde with 2-aminobenzamide resulted in a large amount of ben-
zoic acid as a by-product, while no trace amount of benzoic acid
was detected for the transformation starting with phenylacetic
acid. Apparently, benzaldehyde was readily oxidized to benzoic
acid under these reaction conditions. Indeed, Yin and co-workers
previously utilized phenylacetic acids instead of benzaldehydes
in a one-pot synthesis of quinazolinone [14]. Song and co-
workers employed phenylacetic acids instead of benzaldehydes
in the synthesis of 2-aryl benzothiazoles and benzonitriles
[43,44]. Chaskar and co-workers demonstrated an efficient synthe-
sis of benzoic acids from phenylacetic acids instead of benzaldehy-
des [45].
As previously mentioned, the VNU-21 exhibited higher catalytic
performance than a variety of homogeneous and heterogeneous
catalysts. To additionally highlight the environmetally benign
aspect of this iron-based framework, the readiness of catalyst
recovery and reutilization was consequently studied. The first step
was carried out using 0.3 mmol phenylacetic acid in 0.5 mL DMF at
120 °C for 4 h under an oxygen atmosphere, with 0.01 mmol cata-
lyst. After that, the solid VNU-21 catalyst was removed by centrifu-
gation, 0.20 mmol 2-aminobenzamide in 0.5 mL DMSO was added,
Fig. 4. Catalyst reutilization studies.

T.A. To et al. / Journal of Catalysis 370 (2019) 11–20
17
its crystallinity, though a slight difference was recorded (Fig. 6). No
significant changes were observed in the Fe 2p XPS spectra of the
material before and after the catalysis. Importantly, the ratio of
Fe(II)/Fe(III) in the VNU-21 was found to be unchanged, i.e. approx-
imately 46% based on the area of the deconvoluted Fe 2p3/2 feature
peaks, further indicating that the VNU-21 framework containing
mixed-valence iron species was stable under the applied reaction
conditions (Fig. 7).
The scope of this work was subsequently extended to the syn-
thesis of different quinazolinones via oxidative Csp3AH bond acti-
vation using the VNU-21 catalyst (Table 2). The first step was
conducted using 0.3 mmol phenylacetic acid in 0.5 mL DMF at
120 °C for 4 h under an oxygen atmosphere, with 0.01 mmol cata-
lyst. After that, the solid catalyst was removed, 0.20 mmol 2-
aminobenzamide in 0.5 mL DMSO was added, and the resulting
mixture was heated at 120 °C for 5 h under an oxygen atmosphere.
Following this procedure, 2-phenylquinazolin-4(3H)-one was
achieved in 87% isolated yield (Entry 1). Phenylacetic acids con-
taining an electron-withdrawing substitutent was noticed to be
less reactive, and the reaction time of the second step had to be
extended to 12 h (Entries 2–4). Moving to 2-chlorophenylacetic
acid, 93% yield of 2-(2-chlorophenyl)quinazolin-4(3H)-one was
obtained, though the reaction time of the second step had to be
extended to 18 h (Entry 5). Phenylacetic acids containing an
electron-donating substitutent was more reactive, affording 2-(4-
methoxyphenyl)quinazolin-4(3H)-one (Entry 6) and 2-(3-methoxy
phenyl)quinazolin-4(3H)-one (Entry 7) in 97% and 96% yields,
Fig. 5. FT-IR spectra of the fresh (a) and recovered (b) VNU-21 catalyst.
respectively.
However,
2-o-tolylquinazolin-4(3H)-one
was
obtained in 74% yield for the case of 2-methylphenylacetic acid
(Entry 8). 2-(thiophen-3-yl)acetic acid was also reactive, producing
2-(thiophen-3-yl)quinazolin-4(3H)-one (Entry 9) in 79% yields.
Moving to 2-aminobenzamides containing a substituent, corre-
sponding quinazolinones were also achieved in high yields (Entries
10–12). The research scope was additionally expanded to the syn-
thesis of phenyl benzimidazoles in the presence of the VNU-21 cat-
alyst. Under these conditions, 2-phenyl-1H-benzo[d]imidazole
(Entry 13) was produced in 87% yield from phenylacetic acid and
o-phenylenediamine. Similarly, other phenyl benzimidazoles were
achieved in high yields from substituted o-phenylenediamines
(Entries 14–16). 2-Aminobenzenethiol, and 2-aminophenol were
less reactive towards the one-pot transformation, with 2-
phenylbenzo[d]thiazole (Entry 17), and 2-phenylbenzo[d]oxazole
(Entry 18) being obtained in 60% and 10% yields, respectively.
Fig. 6. X-ray powder diffractograms of the fresh (a) and recovered (b) VNU-21
catalyst.
Fig. 7. Fe 2p XPS spectra of the fresh (a) and recovered (b) VNU-21 catalyst.

18
T.A. To et al. / Journal of Catalysis 370 (2019) 11–20
Table 2
Synthesis of different quinazolinones via oxidative Csp3AH bond activation using VNU-21 catalyst.a
Entry
1
Reactant 1
Reactant 2
Product
Yieldb
87
O
O
COOH
NH2
NH
NH
NH2
N
O
2
3
73c
O
COOH
NH2
Br
NH2
N
O
Br
78c
O
COOH
COOH
NH2
NH
Cl
Cl
NH2
N
O
Cl
Cl
4
5
6
86c
93d
97
O
NH2
NH
NH
NH
NH2
N
O
Cl
O
NH2
COOH
Cl
NH2
N
O
O
COOH
NH2
MeO
MeO
NH2
N
OMe
7
8
96
O
O
COOH
NH2
NH
OMe
NH2
N
O
74c
O
COOH
COOH
NH2
NH
NH2
N
O
9
79d
O
S
NH2
NH
O
S
NH2
O
N
10
90
COOH
NH2
NH2
NH
N

T.A. To et al. / Journal of Catalysis 370 (2019) 11–20
19
Table 2 (continued)
Entry
11
Reactant 1
Reactant 2
Product
Yieldb
87
O
O
N
COOH
COOH
F
F
NH2
NH
NH2
12
90
O
O
Cl
Cl
NH2
NH
NH2
N
13
14
15
87
93
98
NH2
H
N
COOH
COOH
COOH
NH2
NH2
N
H
N
N
NH2
NH2
H
N
l
NH2
NH2
C
N
l
C
16
76
H
COOH
N
N
F
NH2
F
17
18
60
10
SH
S
COOH
COOH
N
O
NH2
OH
N
NH2
a
First step: phenylacetic acid (0.3 mmol), DMF (0.5 mL), VNU-21 (0.01 mmol), 120 °C, 4 h, oxygen atmosphere; second step: 2-aminobenzamides/o-substituted anilines
(0.2 mmol), DMSO (0.5 mL), 5 h, oxygen atmosphere.
b
Isolated yield.
Second step: 12 h.
Second step: 18 h.
c
d
recyclable catalyst was consequently valuable to organic synthesis
and the chemical industry.
4. Conclusions
A new iron-based MOF, VNU-21 (Fe3(BTC)(EDB)2ꢁ12.27H2O),
constructed from mixed-linkers of BTC3ꢀ and EDB2ꢀ with infinite
[Fe3(CO2)7]1 rod SBU, was synthesized and characterized by sev-
eral techniques. The VNU-21 was consequently used as a recy-
clable heterogeneous catalyst in the one-pot synthesis of
quinazolinones via two steps under oxygen atmosphere. The first
step involved the decarboxylation of phenylacetic acids via iron-
catalyzed oxidative Csp3AH bond activation. The second step was
the metal-free oxidative cyclization of intermediate products with
2-aminobenzamides to produce corresponding quinazolinones.
The transformation was remarkably regulated by the solvent, in
which DMF should be used for the first step, while DMSO emerged
as the solvent of choice for the second step. The VNU-21 was more
active towards the one-pot synthesis of quinazolinones than a ser-
ies of heterogeneous and homogeneous catalysts. It was possible to
reutilize the iron-based framework without a considerable deteri-
oration in catalytic performance. The point that quinazolinones
were generated via one-pot sequential transformations with a
Acknowledgements
Thach N. Tu acknowledges the Naval International Cooperative
Opportunities in Science and Technology Program through Project
No. N62909-16-1-2146 for VNU-21 synthesis and characterization.
The catalytic studies were financially supported by the Viet Nam
National Foundation for Science and Technology Development
(NAFOSTED) under Project code 104.05-2017.32.
Appendix A. Supplementary material
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.jcat.2018.11.031.
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