Sustainable parts-per-million level catalysis with FeIII: One-pot cascade synthesis of 2,3-dihydroquinazolin-4(1H)-ones in water

Article abstract of DOI:10.1002/aoc.6116

A silica-supported iron complex has been identified as a highly active and reusable catalyst for the synthesis of medicinally important 2,3-dihydroquinazolin-4(1H)-ones. The catalyst was fully characterized by various spectroscopic analyses such as Fourie

Full text of DOI:10.1002/aoc.6116

Received: 14 October 2020
DOI: 10.1002/aoc.6116
Revised: 19 November 2020
Accepted: 22 November 2020
C O M M U N I C A T I O N
Sustainable parts-per-million level catalysis with FeIII: One-
pot cascade synthesis of 2,3-dihydroquinazolin-4(1H)-ones
in water
Apurba Dutta1
| Priyanka Trivedi2 | Akshay Kulshrestha3
|
Arvind Kumar3 | Vinita Chaturvedi2 | Diganta Sarma1
1Department of Chemistry, Dibrugarh
A silica-supported iron complex has been identified as a highly active
and reusable catalyst for the synthesis of medicinally important
2,3-dihydroquinazolin-4(1H)-ones. The catalyst was fully characterized by vari-
ous spectroscopic analyses such as Fourier-transform infrared spectroscopy
(FT-IR), ultraviolet-visible (UV–VIS), scanning electron microscopy (SEM),
scanning electron microscopy with energy-dispersive X-ray spectroscopy
(SEM–EDX), energy-dispersive spectroscopy (EDS) mapping, X-ray diffraction
(XRD), X-ray photoelectron spectroscopy (XPS), electron paramagnetic
resonance (EPR), inductively coupled plasma atomic emission spectroscopy
(ICP-AES), elemental analysis, Brunauer–Emmett–Teller (BET) isotherm
and thermogravimetric analysis (TGA) analysis. A diverse library of
2,3-dihydroquinazolin-4(1H)-ones including some new analogues were
successfully synthesized in good to excellent yields with parts-per-million
(ppm) levels of Fe using water as a solvent. The active catalyst has high turn-
over number (TON) and turnover frequency (TOF) at the optimized condition,
which were 30,087 and 30,087 h−1, respectively. Ppm level catalysis, wide
substrate scope, shorter reaction time, reusability of the catalyst, green solvent
media and gram-scale synthesis make this protocol eco-friendly and
sustainable.
University, Dibrugarh, 786004, India
2Drug Target Discovery and Development
Division, Central Drug Research Institute,
CSIR, Lucknow, 226001, India
3Salt and Marine Chemicals Division,
CSIR-Central Salt and Marine Chemicals
Research Institute, Bhavnagar, 364002,
India
Correspondence
Diganta Sarma, Department of Chemistry,
Dibrugarh University, Dibrugarh 786004,
India.
Email: dsarma22@gmail.com;
dsarma22@dibru.ac.in
Funding information
Department of Biotechnology, Ministry of
Science and Technology, Grant/Award
Number: BT/PR24684/NER/95/810/2017
K E Y W O R D S
2,3-dihydroquinazolin-4(1H)-ones, C2-symmetric, heterogeneous, parts-per-million, recyclability
1 | INTRODUCTION
counterparts such as recyclability, require less amounts
of catalyst, and so on. Additionally, the former has many
2,3-Dihydroquinazolin-4(1H)-ones are important class of
heterocyclic compounds found in a number of biologi-
cally active as well as naturally occurring pharmaceutical
compounds.[1,2] Various research groups have developed
numerous methodologies for the synthesis of this
important scaffold using different homogeneous and
heterogeneous catalytic systems.[2–4] Heterogeneous cata-
lysts possess some advantages over their homogeneous
advantages over the later, namely, catalyst can be
removed by simple filtration, large surface area and very
importantly the metal contamination with the end prod-
uct is negligible.[5,6] Recently, there are a large number of
heterogeneous catalysts reported by research community
that catalysed different types of valuable organic
reactions.[7–12] Literature study showed that quite a good
number of methods are available for the synthesis of
Appl Organomet Chem. 2020;e6116.
wileyonlinelibrary.com/journal/aoc
© 2020 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.6116

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DUTTA ET AL.
2,3-dihydroquinazolin-4(1H)-ones; multicomponent reac-
tion (MCR) of isatoic anhydride, primary amine or
ammonium acetate and carbonyl compounds is a familiar
one. A vast number of catalytic systems were already
reported by different research groups,[13–22] but these pro-
cedures have some drawbacks such as costly reagents or
catalysts, tedious process, harsh reaction conditions,
elongated time and low product yields. Therefore, efforts
are being made for the development of new catalytic
system that may overcome these boundaries and gives a
new path for the scientific community.
Iron is one the most abundant elements on Earth
having low cost and very high strength that make wide
application of iron in different aspects. Moreover, like
other metals, it has no toxicity issue, and it can be easily
stored for long duration without any special care. Due to
these advantages, iron has been used as catalyst/raw
material in numerous chemical reactions as well as in
many industrial processes.[23–25] In this particular MCR
mentioned above, there were a few methods reported in
literature, which used iron as homogeneous and hetero-
geneous catalysts in different solvent media.[26–28]
Because the exploration of iron catalyst in this particular
reaction is very less, the development of new iron
catalysed strategy with extremely low metal content is of
noteworthy interest. One of the naturally occurring
minerals, silica has been employed in many industrial
processes. The polymerization of silica particles gives a
silica gel that is used in chemical laboratories in large
scale. Silanol groups in their surface, large surface area
and particle size make silica useful in catalyst designing
mainly as support for the metal.[29] Due to the various
advantages, inexpensive nature and easy availability of
the silica gel motivated us to use as support in the current
study. In organic synthesis, solvent media has a signifi-
cant role in the reaction mechanism. From green
chemistry viewpoint, water is the most suitable solvent to
carry out the reactions as it is readily available, economi-
cal, innocuous and non-flammable solvent. Furthermore,
use of water in organic reactions has many advantages
such as improves the reactivities and selectivities,
makes the workup procedures simple, enables the
recycling of the catalyst and allows mild reaction
conditions.[30] Therefore, development of novel synthetic
routes involving silica supported iron catalyst and water
as benign solvent for the synthesis of biologically active
2,3-dihydroquinazolin-4(1H)-ones will be of great impor-
tance among the scientific community. In the present
study, we have developed a simple and convenient
method for the synthesis of 2,3-dihydroquinazolin-4(1H)-
ones through ppm level catalysis with Fe (III). Addition-
ally, we made an attempt to synthesize some novel
2,3-dihydroquinazolin-4(1H)-ones that can be used as
ligands and drugs in forthcoming days.
2 | RESULTS AND DISCUSSION
2.1 | Catalyst preparation
The catalyst was synthesized according to the literature
reported by Hajipour and Azizi.[31] as shown in Figure 1.
At first, 3-chloropropyl trimethoxysilane reacts with
KI in dry acetone under reflux condition to give
FIGURE 1 Synthesis of [{SiO2-
(acac)}3FeIII]Cl3 catalyst

DUTTA ET AL.
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3-iodopropyl trimethoxysilane that further reacts with sil-
ica gel (60–120 Mesh, preheated at 300ꢀC) in dry toluene
for 48 h under reflux temperature. Functionalized silica
was then treated with acetyl acetone and K2CO3 in
CH3CN under reflux temperature to get SiO2-acac sup-
port. Finally, aqueous solution of FeCl3Á6H2O was mixed
with SiO2-acac, prepared in the previous step at room
temperature and obtained a dark orange precipitate.
Then, the solid phase was filtered and washed thoroughly
until no more iron leaching was observed. This dark
orange solid was the resulting catalyst termed as [{SiO2-
(acac)}3FeIII]Cl3.
can be ascribed to the O-H stretching vibration of the
adsorbed water. The peaks appearing at 1,579, 1,521,
1,435, 1,356 and 671 cm−1 of [{SiO2-(acac)}3FeIII]Cl3 can
be correlated to the acetyl acetone ligand coordinated to
iron. All these characteristic bands were also found in the
FT-IR spectrum of SiO2-acac (with slight shifting)
(Figure 2).[32–34]
The ultraviolet-visible (UV–VIS) spectra of the silica
and modified silica supported catalyst are shown in
Figure 3. In the UV spectrum of the catalyst, two absorp-
tion bands are observed at 365 and 478 nm clearly
confirming the presence of iron in the catalyst.[35] A band
at 265 nm was observed in the spectrum due to the pres-
ence of modified silica support in the catalyst.[36] Because
functionalized silica was used as a support in the catalyst,
the band is shifted to lower wavelength (blue shift) as
compared with silica (283 nm). The content of Fe in the
catalyst was investigated by inductively coupled plasma
atomic emission spectroscopy (ICP-AES) analysis. The Fe
content of the prepared silica supported catalyst was
found to be 4.03 × 10−5 mmol g−1 (0.00023 wt%). The
elemental analysis (CHN) of the prepared catalyst was
performed and found that carbon, hydrogen and nitrogen
contents of the catalyst were 3.70%, 1.692% and 0.00%,
respectively.
The morphology of the silica and catalyst was studied
by scanning electron microscopy (SEM) shown in
Figure 4a,b. The SEM image clearly showed
irregular polyhedron morphology of the catalyst. The
energy-dispersive X-ray spectroscopy (EDX) spectra of
[{SiO2-(acac)}3FeIII]Cl3 clearly indicated the presence
of C, O, Si and Fe (Figure 4c vs. Figure 4d) in the catalyst,
which confirmed the immobilization of Fe on the surface
of modified SiO2. The iron concentration was found to be
2.2 | Characterization
In the Fourier-transform infrared spectroscopy (FT-IR)
spectrum of silica, an absorption band appearing at
3,780 cm−1 ascribe to Si-OH stretching vibration, which
is absent in the modified silica samples and in the final
catalyst. The two characteristic peaks at 1,078 and
804 cm−1 are due to the symmetrical and asymmetrical
vibrations of Si-O-Si, respectively. The two small bands
around 2,892 and 2,828 cm−1 found in the spectrum of
SiO2-silane are due to the asymmetric and symmetric
C-H stretching of the alkyl groups. These two peaks were
also observed in the catalyst with slight shifting of the
vibration bands. A band around 1,635 cm−1 of SiO2-silane
FIGURE 2 FT-IR spectra of modified silica samples and
[{SiO2-(acac)}3FeIII]Cl3 catalyst
FIGURE 3 UV–VIS spectra of silica and [{SiO2-(acac)}3FeIII
]
Cl3 catalyst

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DUTTA ET AL.
FIGURE 4 SEM images of
(a) silica, (b) [{SiO2-(acac)}3FeIII]Cl3 and
EDX patterns of (c) silica, (d) [{SiO2-
(acac)}3FeIII]Cl3
different in different areas that were observed when two
different areas were selected for EDX analysis. Further-
more, EDS mapping images of the catalyst indicated the
presence of uniformly dispersed Fe, C, O and Si in their
structure (Figure 5).
Further, X-ray diffraction (XRD) pattern analysis of
the catalyst provided more evidence for the presence of
iron in the modified silica support (Figure 6). A broad
peak at around 2θ = 22.2ꢀ corresponding to the (001) is
ascribable to amorphous silica support.[37] The other
characteristic diffraction peaks was found at 2θ values of
35.3ꢀ and 62.2ꢀ, which are assigned to (311) and (440)
planes of iron (III), respectively.[38]
In order to confirm the elements valence state of all
the species in the catalyst, X-ray photoelectron spectros-
copy (XPS) analysis was performed. From the survey
spectrum of the catalyst, it was confirmed that element
carbon was present in the catalyst. The peak appearing at
293.54 eV was assigned to C 1s of carbon species, which
was obtained due to the presence of acetyl acetone and
propyl moiety in the active catalyst (Figure 7a). The
binding energy of Fe 2p3/2 and 2p1/2 at 711.42 and
724.85 eV, respectively, in the XPS supported that Fe (III)
is present in the prepared catalyst (Figure 7b).[38,39] The
presence of SiO2 in the catalyst was confirmed by the
peak at 103.29 eV assigned to Si 2p (Figure 7d).
FIGURE 5 EDS mapping images of (a) Fe,
(b) C, (c) O and (d) Si of the catalyst

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FIGURE 8 EPR spectrum of Fe in [{SiO2-(acac)}3FeIII]Cl3
FIGURE 6 Powder XRD patterns for (a) SiO2 and (b) [{SiO2-
(acac)}3FeIII]Cl3
The N2 adsorption–desorption isotherms of the silica
and all modified samples were calculated by using N2
adsorption at 77 K shown in Figure 9. All the modified
samples showed similar types of isotherm (type IV) as
that of silica with typical hysteresis loop, which is a char-
acteristic feature of highly ordered mesoporous materials.
The surface area, pore volume and pore diameter of all
the samples obtained from N2 sorption isotherms are
compiled in Table 1. Functionalization of silica signifi-
cantly affected the surface area and pore distribution of
modified samples. The Brunauer–Emmett–Teller (BET)
Additionally, the XPS peak at 532.5 eV corresponds to
the O 1s, clearly indicating the presence of silica bound
silanol groups (Figure 7c).
The XRD and XPS data were further supported by
electron paramagnetic resonance (EPR) analysis of the
catalyst, which was recorded at room temperature
(Figure 8). The g values of [{SiO2-(acac)}3FeIII]Cl3 catalyst
from the EPR spectrum was found to be 4.31 and 2.00,
indicated that iron is present in +3 oxidation state in the
silica supported catalyst.[40]
FIGURE 7 XPS spectra of (a) C
1s, Sat, (b) Fe 2p3/2 and 2p1/2 (c) O 1s
and (d) Si 2p of [{SiO2-
(acac)}3FeIII]Cl3

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DUTTA ET AL.
organic components as well as the absorbed water and
found to be 0.03847 mmol g−1 on SiO2 surface.
2.3 | Catalytic application
To show the advantage of the prepared catalyst in organic
synthesis, at first, the catalyst was applied for the reaction
of isatoic anhydride, aniline and 4-chlorobenzaldehyde
affording 2,3-dihydroquinazolin-4(1H)-one. When 20 mg
the prepared catalyst was used for the reaction at 100ꢀC,
the desired product was obtained in quantitative yield
within an hour (Table 2, entry 2). Four other types of iron
sources were also employed as catalysts for this reaction,
but the yield of the reaction was not satisfactory (Table 2,
entries 3–6). The reaction was also carried out with SiO2
and SiO2-acac as catalysts; however, no suitable results
were obtained (Table 2, entries 7 and 8). Then, some
adjustments to the reaction conditions were made to get
the optimized result by using the prepared heterogeneous
catalyst. At first, different types of solvents were exam-
ined for this reaction and found that water gives excellent
yield of the product within short period of time (Table 2,
entry 2 vs. entries 9–16). The reaction was also performed
in the absence of solvent media, but no satisfactory yield
was observed, which confirmed the importance of solvent
in the reaction (Table 2, entry 17). In absence of the cata-
lyst, the reaction afforded only 30% yield of the desired
product (Table 2, entry 1). Further, the amount of the cat-
alyst was optimized and observed that 20 mg of the
catalyst (32.24 ppm Fe) was sufficient for quantitative
yield of 2,3-dihydroquinazolin-4(1H)-one (Table 2, entry
20 vs. entries 18 and 19). The temperature of the reaction
was also investigated and found that 80ꢀC was well
enough for the reaction to takes place within an hour
(Table 2, entry 20). Finally, the turnover number (TON)
and turnover frequency (TOF) of the catalyst were also
calculated for the model reaction based on the amount of
active Fe used, and they were found to be 30,087 and
30,087 h−1, respectively (Table 3, entry 1).
FIGURE 9 N2 adsorption–desorption isotherms of silica and
modified silica samples
surface area decreased from SiO2 (396.69 m2 g−1) to
[{SiO2-(acac)}3FeIII]Cl3 (273.93 m2 g−1), which clearly
indicates the successful incorporation of iron over modi-
fied silica support.[41] On the other hand, the pore diame-
ter initially decreased from SiO2 (5.24 nm) to SiO2-silane
(4.01 nm) and then increased to [{SiO2-(acac)}3FeIII]Cl3
(5.24 nm).
Thermogravimetric analysis (TGA) was applied to
investigate the thermal behaviour of the synthesized cata-
lyst from room temperature to 800ꢀC. There are three
main weight losses (shown in Figure S1). Firstly, the
weight loss (8.74%) at around 100ꢀC–280ꢀC is allocated to
physically and hydrogen bonded water on the silica
support and decomposition of some organic parts
anchored on SiO2. As the melting point of Fe (acac)3 is
180ꢀC–181ꢀC, thereafter, it may get decomposed to small
fractions. The other two weight losses (5.15% and 4.54%)
in the range of 280ꢀC–600ꢀC is related to the modified
organic parts that are anchored to SiO2 surface. Because
the first weight loss included organic components of the
catalyst, loading of the complex on SiO2 was calculated
by taking the total weight loss (18.43%) that includes the
After obtaining the optimum reaction conditions
mentioned above (Table 2, entry 17), we explored the
applicability of the system to a wide variety of amines
TABLE 1 Characterization of
silica and modified silica samples by N2
Catalyst
SiO2
396.69
0.519
5.24
SiO2-Silane
332.61
0.334
[{SiO2-(acac)}3FeIII]Cl3
BET surface areaa (m2 g−1) (ABET
Total pore volumeb (cm3 g−1) (VP)
Pore diameterc (nm)
)
272.93
adsorption–desorption measurement
0.358
5.24
4.01
Abbreviation: BET, Brunauer–Emmett–Teller.
aThe BET method used in N2 sorption.
bSingle-point porevolume at P/P0 = 0.994.
cAdsorption average pore diameter (by the BET method).

DUTTA ET AL.
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TABLE 2 Optimization of reaction conditions
Entry
1
Catalyst (mol%)
Solvent
H2O
Temperature (ꢀC)
Time (h)
Yielda (%)
—
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
1
30
98
2
[{SiO2-(acac)}3FeIII]Cl3 (0.003224)
H2O
1
3
Fe powder (90)
H2O
1
70
4
FeCl3 (5)
H2O
1
60
5
FeCl2 (5)
H2O
1
50
6
Fe (acac)3 (5)
H2O
1
75
7
8b
SiO2 (5)
H2O
1
35
SiO2-(acac)
H2O
1
30
9
[{SiO2-(acac)}3FeIII]Cl3 (0.003224)
[{SiO2-(acac)}3FeIII]Cl3 (0.003224)
[{SiO2-(acac)}3FeIII]Cl3 (0.003224)
[{SiO2-(acac)}3FeIII]Cl3 (0.003224)
[{SiO2-(acac)}3FeIII]Cl3 (0.003224)
[{SiO2-(acac)}3FeIII]Cl3 (0.003224)
[{SiO2-(acac)}3FeIII]Cl3 (0.003224)
[{SiO2-(acac)}3FeIII]Cl3 (0.003224)
[{SiO2-(acac)}3FeIII]Cl3 (0.003224)
[{SiO2-(acac)}3FeIII]Cl3 (0.001612)
[{SiO2-(acac)}3FeIII]Cl3 (0.002418)
[{SiO2-(acac)}3FeIII]Cl3 (0.003224, 32.24 ppm Fe)
[{SiO2-(acac)}3FeIII]Cl3 (0.002418)
[{SiO2-(acac)}3FeIII]Cl3 (0.003224)
CH3CN
EtOH
Dry toluene
DMSO
DMF
DCM
EtOAc
THF
1.5
2
—
20
10
11
12
13
14
15
16
17
18
19
20
21
22
2
20
1.5
1.5
1.5
1.5
1.5
1.5
1
—
—
—
—
trace
50
—
H2O
80
H2O
1
90
H2O
1
97
H2O
80
1
90
H2O
70
1
60
Note. Reaction conditions: isatoic anhydride (1 mmol), aniline (1.2 mmol), 4-chlorobenzaldehyde (1.2 mmol), catalyst (n mol% of Fe) and solvent (2 ml) were
stirred at different temperature.
aIsolated yield.
b20 mg of SiO2-(acac) was used.
TABLE 3 TON and TOF of the
catalyst for the model reaction
[{SiO2-(acac)}3FeIII]Cl3
Time (h)
Yielda (%)
TONb
30,087
37,221
49,628
TOFc (h−1
30,087
)
#
Entry
1
2
3
32.24
24.18
16.12
1
1
1
97
90
80
37,221
49,628
Note. Reaction conditions: isatoic anhydride (1 mmol), aniline (1.2 mmol), 4-chlorobenzaldehyde
(1.2 mmol), [SiO2-(acac)]3FeIIICl3(n ppm) and water (2 ml) were stirred at 80ꢀC.
Abbreviations: TOF, turnover frequency; TON, turnover number.
aIsolated yield.
bmmol of product per mmol of catalyst.
cTON per unit time.
#(0.1 mol% = 1,000 ppm).

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DUTTA ET AL.
TABLE 4 Synthesis of various disubstituted 2,3-dihydroquinazolin-4(1H)-ones
2a, 1 h, 97%
2b, 1 h, 98%
2c, 1.5 h, 98%
2d, 2 h, 95%
2e, 2 h, 90%
2f, 2 h, 95%
2g, 2 h, 96%
2h, 2 h, 98%
2i, 2 h, 95%
2j, 2 h, 95%
2k, 2.5 h, 62%
2l, 2.5 h, 85%
2m, 2 h, 58%
2n, 2 h, 55%
2o, 2 h, 56%
2p, 2 h, 98%
2q, 2 h, 98%
2r, 4 h, 95%
2s, 5 h, 92%
2t, 4 h, 95%
(Continues)

DUTTA ET AL.
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TABLE 4 (Continued)
2u, 5 h, 75%
2v, 4 h, 72%
Note. Reaction conditions: isatoic anhydrides (1 mmol), anilines (1.2 mmol), benzaldehydes (1.2 mmol), [{SiO2-(acac)}3FeIII]Cl3 (20 mg, 32.24 ppm Fe) in water
(2 ml) were stirred at 80ꢀC.
and aldehydes (Table 4). First, the impact of substituted
aromatic amine and aldehyde groups were investigated
and found that a range of 2,3-dihydroquinazolin-4(1H)-
ones were formed in good to excellent yields (Table 4,
2a–2o). Furthermore, aliphatic amine was applied in this
reaction and gives almost quantitative yields of desired
products (Table 4, 2p and 2q). We have also investigated
propargyl amine with different substituted aromatic alde-
hydes and gives excellent yield of products in slightly
longer period of time (Table 5, 3a–3e). These five reac-
tions (Table 5) were performed in gram scale to demon-
strate the industrial utility of the methodology. The
reaction of isatoic anhydride derivative (5-chloroisatoic
anhydride) was also investigated in this study, and mod-
erate yield of 2,3-dihydroquinazolin-4(1H)-ones were
obtained within 5 h (Table 4, 2r–2v).
Further, the above methodology was applied for the
reaction of isatoic anhydride, ammonium acetate and
TABLE 5 Gram-scale syntheses of various novel 2,3-dihydroquinazolin-4(1H)-ones
Note. Reaction conditions: isatoic anhydride (1.63 mg, 10 mmol), propargyl amine (0.66 mg, 12 mmol), benzaldehydes (12 mmol), [{SiO2-(acac)}3FeIII]Cl3
(200 mg, 32.24 ppm Fe) in water (20 ml) were stirred at 80ꢀC.

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DUTTA ET AL.
TABLE 6 Syntheses of monosubstituted 2,3-dihydroquinazolin-4(1H)-ones
Note. Reaction conditions: isatoic anhydrides (1 mmol), NH4OAc (1.2 mmol), aldehydes (1.2 mmol), [{SiO2-(acac)}3FeIII]Cl3 (20 mg, 32.24 ppm Fe) in water
(2 ml) were stirred at 80ꢀC.
different carbonyl derivatives. Substituted benzaldehydes
give excellent yields of desired products within
1–2 h (Table 6). Aldehyde containing heterocyclic
ring and aliphatic aldehyde also give the desired
2,3-dihydroquinazolin-4(1H)-ones within short period of
time (Table 6, 4g–4h). Similarly ketones also gave
excellent yields of the products within an hour (Table 6,
4i–4j).
Finally, the recyclability of the prepared catalyst was
investigated by using isatoic anhydride, aniline and
4-chlorobenzaldehyde as the model reaction. After
completion of the reaction, the catalyst was recovered by
centrifugation, followed by washing with water and ace-
tone to remove the reaction products from the catalyst.
Then, the catalyst was dried in oven and directly reused
for next run without further purification. The catalyst
TABLE 7 Reusability of the [{SiO2-
(acac)}3FeIII]Cl3 for the synthesis of
2,3-dihydroquinazolin-4(1H)-ones
Run
1
2
3
4
5
Yieldb (%)
97
95
95
92
88
Note. Reaction conditions: Isatoic anhydride (1 mmol), aniline (1.2 mmol), 4-chlorobenzaldehyde
(1.2 mmol), [{SiO2-(acac)}3FeIII]Cl3 (20 mg, 32.24 ppm Fe) in water (2 ml) were stirred at 80ꢀC.
bIsolated yield.

DUTTA ET AL.
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performed in which the catalytically active particles were
removed from the reaction mixture by filtration after
30 min, and the isolated yields of the reaction was found
to be 42%. Then, the filtrate was allowed to continue the
reaction without the solid catalyst for additional 3 h.
After removal of the catalyst particles, the reaction did
not proceed, indicating that no catalytically active Fe
remained in the filtrate.
2.4 | Structure of the catalyst
In the last step of the preparation of [{SiO2-(acac)}3FeIII]
Cl3, the colour changes from colourless to dark orange,
which may be due to the formation of Fe (acac)3.
According to the literature reports,[32,42] the colour and
coordination geometry of the Fe (acac)3 is red and
octahedral, respectively. Since in [{SiO2-(acac)}3FeIII]Cl3
catalyst, SiO2 was used as support that was attached
with the FeIII(acac)3 so the coordination geometry of the
catalyst should be octahedral in nature (Figure 10).
Again, because the oxidation state of Fe in the
catalyst was +3, which was confirmed by XPS, XRD
and EPR analyses, Fe must form Fe (acac)3 in the
final catalyst, which was anchored with silica
support. Due to the presence of silica support in the
catalyst, the colour of the complex changes from red to
dark orange.
FIGURE 10 Structure of [{SiO2-(acac)}3FeIII]Cl3
was reused for five cycles, and the catalytic results are
listed in Table 7. The yields were almost identical in all
the five cycles, confirming that the catalyst was very
active, stable and reusable up to fifth cycle. Further,
leaching of the iron species from the support was exam-
ined by ICP-AES analysis of reused catalyst. From the
ICP-AES analysis, no significant leaching of iron was
observed from the catalyst. Further, hot filtration test was
SCHEME 1 Plausible reaction
mechanism

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DUTTA ET AL.
TABLE 8 Synthesis of various novel bis-2,3-dihydroquinazolin-4(1H)-ones
Note. Reaction conditions: 3a–3e (1 mmol), piperidine (1 equiv) and Cu(OAc)2ÁH2O (10 mol%) in CH2Cl2 were stirred at room temperature.
2.5 | Plausible reaction mechanism
ones through Glaser coupling reaction using 3a–3e as
starting precursors.44 As per our expectation, the desired
The reaction was initiated by the interaction of carbonyl
group of isatoic anhydride with the iron atom of [{SiO2-
(acac)}3FeIII]Cl3 through a chemical bond. A vacant site
was generated by dissociating one of the oxygen atoms of
acetylacetonate ligand from the iron centre, which may
be due to the hemilability[43] of one of the side arms of
acetylacetonate that activates the anhydride molecule.
After the activation of isatoic anhydride, the iron com-
plex was regenerated. Then, the lone pair of primary
amine attacks the carbonyl carbon of the anhydride to
produce a reactive intermediate I, which in turn gener-
ates intermediate II by the release of one molecule of
CO2. Afterwards, key intermediate III is afforded by the
proton transfer reaction. Subsequently, the catalyst acti-
vates the carbonyl compound in the similar way and
reacts with intermediate III to produce the imine inter-
mediate IV. Finally, nucleophilic attack of amide nitro-
gen takes place on the electron-deficient imine carbon,
followed by a 1,5-proton shift affording the target product
2,3-dihydroquinazolin-4(1H)-one (Scheme 1).[22,26]
novel
2,3-dihydroquinazolin-4(1H)-one
molecules
were obtained in moderate to good yields (Table 8,
entries 5a–e). All the five compounds are C2-symmetric,
which was confirmed by NMR spectroscopy.
C2-symmetric molecules have been used in different
catalytic reactions as ligands because they limit the
numbers of side reaction. Therefore, these molecules are
also expected to have wide applicability in different types
of organic reactions in near future.
3 | CONCLUSIONS
In summary, we disclosed a methodology for the synthe-
sis of 2,3-dihydroquinazolin-4(1H)-ones via one pot mul-
ticomponent reaction of isatoic anhydrides, amines or
ammonium acetate and carbonyls using ppm level of Fe
in H2O. Highly abundant and inexpensive nature of iron,
ppm level catalysis, gram-scale synthesis of novel com-
pounds, aqueous solvent media, short reaction period
and reusability of the catalyst up to fifth cycle are the
merits and novelty of the current protocol. Furthermore,
we designed and successfully executed synthesis of some
After getting a wide variety of 2,3-dihydroquinazolin-
4(1H)-one molecules, we have extended our work for the
synthesis of some novel 2,3-dihydroquinazolin-4(1H)-

DUTTA ET AL.
13 of 14
novel C2 symmetric bis-2,3-dihydroquinazolin-4(1H)-one
derivatives via Glaser coupling. All the five C2-symmetric
molecules can be used as ligands in different organic
reactions in upcoming days. A total of 42 products library
were synthesized in the present study, 15 of which were
novel analogues that may be used as potential drug
candidates in near future.
research grant (BT/PR24684/NER/95/810/2017). AD
thanks DBT, New Delhi for Research Fellowship. The
financial assistance of UGC-SAP programme to the
Department of Chemistry, Dibrugarh University is also
gratefully acknowledged. The authors gratefully
acknowledge STIC Cochin, IISc Bangalore and CSIC
Dibrugarh University for spectral data.
AUTHOR CONTRIBUTIONS
4 | EXPERIMENTAL
Apurba Dutta: Conceptualization; data curation; formal
analysis; methodology; software. Priyanka Trivedi:
Data curation; formal analysis; methodology. Akshay
Kulshrestha : Data curation; formal analysis; methodol-
ogy. Arvind Kumar: Formal analysis. Vinita
Chaturvedi: Formal analysis; methodology. Diganta
Sarma: Conceptualization; supervision.
4.1 | Preparation of SiO2-silane
The catalyst was synthesized according to the literature
reported by Hajipour et al.[31] For preparation of
SiO2-silane, 3-chloropropyl trimethoxysilane reacts with
KI in dry acetone under reflux condition to give
3-iodopropyl trimethoxysilane that further reacts with a
silica gel (60–120 Mesh, preheated at 300ꢀC) in dry tolu-
ene for 48 h under reflux temperature. Then, the solvent
was decanted, and the silica was washed thoroughly with
toluene, before transferring to a Soxhlet thimble and
ORCID
Apurba Dutta https://orcid.org/0000-0002-5677-7252
Diganta Sarma https://orcid.org/0000-0001-5174-418X
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How to cite this article: Dutta A, Trivedi P,
Kulshrestha A, Kumar A, Chaturvedi V, Sarma D.
Sustainable parts-per-million level catalysis with
FeIII: One-pot cascade synthesis of 2,3-
dihydroquinazolin-4(1H)-ones in water. Appl
Organomet Chem. 2020;e6116. https://doi.org/10.
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