Eco-friendly synthesis of 2,3-dihydroquinazolin-4(1H)-ones catalyzed by FeCl3/Al2O3 and analysis of large1H NMR diastereotopic effect

Article abstract of DOI:10.21577/0103-5053.20180161

In the present study, we have carried out a condensation reaction for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones from 2-amino-N-benzylbenzamide and different aromatic aldehydes using FeCl₃ catalyst supported on Al₂O₃. It was demonstrated that this material can be used successfully for the nucleation of quinazolinones with good to excellent yield; furthermore, the FeCl₃/Al₂O₃ catalyst can be recovered and reused. This catalyst was used before in the synthesis of imidazole with very good yields. The synthesized quinazolinones showed a large range diastereotopic effect over the methylene group and, this anomalous difference was studied through nuclear magnetic resonance (NMR) and computational calculations.

Full text of DOI:10.21577/0103-5053.20180161

http://dx.doi.org/10.21577/0103-5053.20180161
J. Braz. Chem. Soc., Vol. 00, No. 00, 1-8, 2018
Printed in Brazil - ©2018 Sociedade Brasileira de Química
Article
Eco-Friendly Synthesis of 2,3-Dihydroquinazolin-4(1H)-ones Catalyzed by
FeCl3/Al2O3 and Analysis of Large 1H NMR Diastereotopic Effect
Isabel Monreal,a Mariano Sánchez-Castellanos,b Karla Ramírez-Gualito,c
Gabriel Cuevas,d Karla A. Espinozaa and Ignacio A. Rivero*,a
aCentro de Graduados e Investigación, Instituto Tecnológico de Tijuana,
22414 Tijuana, B.C., Mexico
bFacultad de Química de la Universidad Autónoma de México (UNAM),
Circuito Exterior s/n, Ciudad Universitaria, 04510 Mexico City, Mexico
cInstituto de Química, Universidad Nacional Autónoma de México (UNAM),
Circuito Exterior s/n, Ciudad Universitaria, 04510 Mexico City, Mexico
dCentro de Nanociencias y Micro y Nanotecnologías, Instituto Politécnico Nacional,
Av. Luis Enrique Erro s/n, Unidad Profesional Adolfo López Mateos, Zacatenco,
07738 Mexico City, Mexico
In the present study, we have carried out a condensation reaction for the synthesis of
2,3-dihydroquinazolin-4(1H)-ones from 2-amino-N-benzylbenzamide and different aromatic
aldehydes using FeCl3 catalyst supported on Al2O3. It was demonstrated that this material can be
used successfully for the nucleation of quinazolinones with good to excellent yield; furthermore,
the FeCl3/Al2O3 catalyst can be recovered and reused. This catalyst was used before in the
synthesis of imidazole with very good yields. The synthesized quinazolinones showed a large
range diastereotopic effect over the methylene group and, this anomalous difference was studied
through nuclear magnetic resonance (NMR) and computational calculations.
Keywords: quinazolinone, 2-amino-N-benzylbenzamide, diastereotopic, eco-friendly
Introduction
mutase,11 as potent antitumor agents that inhibit tubulin.12
They have been evaluated as anticancer agents,13,14 for
insecticidal,15 antibacterial16,17 and antifungal18 activity.
Additionally, these compounds can easily be oxidized to
their quinazolin-4(3H)-one analogs, which are biologically
active compounds.19 Thus, an efficient synthesis of these
compounds has been of great interest in past years.20 There
have been developed different methods of synthesis for
2,3-dihydroquinazolin-4(1H)-ones (DQZ) most recently;
MnIII-based reaction,21 under ultrasonic irradiation,22 zeolite
catalyzed method,23 with green chemistry using nano-
indium oxide24 and carbon nanotubes as a heterogeneous
catalyst,25 etc.26-31 QZ skeleton is very common in many
natural alkaloids.32-34 Keeping in view the above, we
report a convenient and high yield eco-friendly synthesis
of QZ using FeCl3/Al2O3 as catalyst; FeCl3/Al2O3 could be
recovered and reused.
Quinazolinone (QZ) heterocycles and their derivatives
are a very important group of molecules. One of the first
QZ’s synthesized was methaqualone (Figure 1), originally
used as an antimalarian drug.1 The sedative-hypnotic
activity of methaqualone was observed since 1951;
and later was used for the treatment of insomnia, as a
sedative and muscle relaxant.2 QZ’s have a wide extent of
biological actions3 such as central nervous system activity,4
anticonvulsant and antidepressant agents,5 they have
been used for biological evaluation and docking studies
(Alzheimer’s disease),6 in nuclear medicine as potential
labeler.7 Their analgesic and anti-inflammatory properties
have been evaluated8 in endocrinology as inverse agonist
for the human thyroid-stimulating hormone receptor,9
as enzymatic inhibitors of thermolysin10 and chorismate
*e-mail: irivero@tectijuana.mx

2
Eco-Friendly Synthesis of 2,3-Dihydroquinazolin-4(1H)-ones Catalyzed by FeCl3/Al2O3
J. Braz. Chem. Soc.
and FeCl3/Al2O3 (160 mg) were placed. It was capped and
shook for 2 h, the reaction was followed by TLC and filtered
by gravity. The residues were washed with ethyl acetate,
the solvent was eliminated to reduced pressure, the solid
obtained was purified by chromatography column, eluted
with petroleum ether and EtOAc. The recovery percentage
were between 85-98%.
Figure 1. 2-Methyl-3-o-tolyl-4(3H)-quinazolinone (1).
Experimental
Results and Discussion
Computational methods
Synthesis of quinazolinones
A molecular mechanics conformational analysis of
compounds 3b, 3f and 3h was done with the CompúteVOA35
commercial software. The most stable conformers were
optimized at the mPW1B95/6-311+G(2d,p) level of theory
with Gaussian 09.36 The charge and electronic delocalization
index were calculated with the wave function obtained from
the optimization using the AIMAll software.37
The ortho-aminobenzamide (OAB) (2) is a precursor
of several types of compounds with biological activity.
Initially, we prepare 2 from the isatoic anhydride and
benzylamine in dimethylformamide (DMF) at 60 °C,
allowing the formation of CO2.38 The 2 was obtained in
quantitative yield.
In our group, imidazole compounds were prepared
with the FeCl3/Al2O3 catalyst, obtaining very good yields.39
This methodology was used to prepare the QZ and only
produced DQZ in all cases. It was necessary to oxidize
with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to
obtain the QZ. The synthesis of DQZ was carried out with
OAB and different benzaldehydes as a starting material in
MeOH, using the base reaction shown on Table 1.
The catalyst was prepared with a reported methodology,40
and the reactions were carried out at room temperature,
during 4 h, to afford compounds 3a-3i (Table 1). The nine
DQZ were obtained in good to excellent yields (Table 1).
In Scheme 1, a plausible mechanism is shown that begins
with the preparation of the catalyst. The FeCl3 and the silica
are mixed in an acetone solution, the solvent is removed and
the FeCl3/silica gel was dried. The FeCl3 was adsorbed on the
surface of the silica, the chloride ion occupying some vacancy
of the surface causing the ferric salt to behave in ionic form.
This effect of synergism due to the dissociation of the iron
salt in its ionized form, increases the catalytic capacity. The
Fe + salt interacts on the oxygen of the aldehyde (Scheme 1a)
catalyzing the condensation of OAB to form the imine
and, subsequently, this catalyst acts on the amide oxygen
promoting the equilibrium with the imidic acid, which was
condensed to form the imidazolinone.
General procedures
Thin-layer chromatography (TLC) was performed
on silica gel F254 plates (Merck). All compounds were
detected using UV light. Melting points were obtained on
an Electrothermal 88629 apparatus and are not corrected.
Infrared spectra (IR) were recorded on a PerkinElmer
1
FT-IR 1600 spectrometer. H and 13C nuclear magnetic
resonance (NMR) spectra at 200 and 50 MHz, respectively,
were recorded on aVarian Mercury 200 MHz Spectrometer
in CDCl3 and/or dimethyl sulfoxide (DMSO-d6) with
tetramethylsilane (TMS) as internal standard. Mass spectra
were obtained on an Agilent Technologies 5975C MS
Spectrometer at 70 eV by direct insertion. Diffraction data
were collected on a Smart Apex X-ray diffractometer.
General method for preparing catalyst FeCl3/Al2O3
In a flask, FeCl3 (18.6 g, 11.4 mmol), Al2O3 (acid
alumina, 10.0 g, 98.0 mmol) were placed in acetone
(17 mL) and the reaction mixture was stirred constantly
for 1 h. The acetone was removed under reduced pressure,
then the catalyst was dried at 120 °C for 12 h in an oven
under reduced pressure (equation 1).19
1H NMR characterization
(1)
The DQZ has a chiral center that modifies the benzyl
methylene protons and makes them diastereotopic protons.
These protons show a difference from 1.4 to 1.9 ppm
(Table 2), which is very large and unusual, so it is an
important fact to highlight (Figure 2).
General method for preparing quinazolinones (3a-3i)
In a vial, 2-amino-N-benzylbenzamide (100.0 mg,
0.450 mmol), aldehyde (0.450 mmol), MeOH (2 mL),

Vol. 00, No. 00, 2018
Monreal et al.
3
Table 1. Synthesis of DQZ (3) from OAB (2)
Aldehyde
(1 equiv.)
entry
1
Product
Yield / % entry
Aldehyde
Product
Yield / %
98
98
6
7
95
2
93
3
4
5
97
95
85
8
9
98
97
1
The H NMR spectrum of compound 3b shows two
diastereotopic protons (proR and proS) with a chemical shift
of 3.81 and 5.31 ppm, respectively. This is an unusual fact
for this kind of protons and is due to the existence of a stable
rotamer that makes this difference so relevant (Figure 3).
The geometrical properties of the molecules around
the methylene group were determined by X-ray structures.
Initially, the atom bonds length values were obtained: in
the segment C(4)−N(3)−C(23), the C23 corresponds to the
methylene carbon where the diastereotopic hydrogens are
located, in 3f, is the C25. Table 2 shows that compound 3i
has the largest chemical shift difference and has the shorter
distances. The O(1)−C(4) and the N(3)−C(23) bonds
distances are illustrative, it is shown that they have a very
important role in the difference of the chemical shift of
the diastereotopic hydrogens. When the O−C and N−C
bond distances diminish, the chemical shift difference is
large, with values between 1.5 and 1.9 ppm. The dihedral
angle is an indication of the spatial arrangement, the
negative value of the dihedral angle (O−C−N−C) affects
the difference between the diastereotopic hydrogens.
X-ray diffraction structures
In Figure 4, the ORTEP structures of compounds 3b, 3d,
3f, 3g and 3i are shown. The bond lengths and angles related
to the carbonyl group, the nitrogen bonded to this group and
the methylene group that contains the two diastereotopic
protons (proR and proS) were analyzed.
These molecules exhibit an unusual shift of the
methylene hydrogens, which is too large for diastereotopic
hydrogens. Such large differences are associated to charge
transfer as is explained by computational calculation.

4
Eco-Friendly Synthesis of 2,3-Dihydroquinazolin-4(1H)-ones Catalyzed by FeCl3/Al2O3
J. Braz. Chem. Soc.
Scheme 1. Mechanism proposed in the synthesis of quinazolinone 3.
Computational analysis
In order to explain the chemical shifts determined for
the protons proR and proS, a conformational analysis at the
molecular mechanic’s level was done with the computeVOA
software. In Figure 5, a selection of the most stable
conformers of compound 3b is shown. These conformers
were optimized at the mPW1B95/6-311+G(2d,p) level
of theory. The most important difference between these
Figure 2. Diastereotopic protons in benzyl methylene of the DQZ.
Figure 3. 1H NMR spectrum of compound 3b showing the differences in diastereotopic protons d and e.

Vol. 00, No. 00, 2018
Monreal et al.
5
Figure 4. ORTEP structures of 3b, 3d, 3f, 3g and 3i crystals.
Table 2. X-ray and 1H NMR data
Bond length / Å
Structure
Dihedral angle / degree
1H NMR d / ppm
O(1)−C(4)
N(3)−C(4)
N(3)−C(23)
O(1)−C(4)−N(3)−C(23)
C(4)−N(3)−C(23)−H(23e)
1.2478(19)
1.341(2)
1.462(2)
−3.38
135.42
1.5
1.2546(16)
1.237(2)
1.3466(17)
1.362(2)
1.4705(17)
1.460(2)
−3.24
114.26
145.05
1.5
1.6
−10.89
1.259(8)
1.355(9)
1.357(2)
1.467(8)
1.452(2)
0.61
139.93
135.63
1.4
1.9
1.230(18)
−4.57
NMR: nuclear magnetic resonance.

6
Eco-Friendly Synthesis of 2,3-Dihydroquinazolin-4(1H)-ones Catalyzed by FeCl3/Al2O3
J. Braz. Chem. Soc.
Figure 5. Lower energy conformers of compound 3b optimized at the level of theory mPW1B95/6-311+G(2d,p). Energy values (E), zero point energy (ZPE)
in Hartrees and the number of imaginary frequencies (Nimag) are included. Nimag = 0 refers to a structural minimum.
Table 4. Charges of oxygen and hydrogens proR and proS calculated
with AIM using the functional mPW1B95 and the 6-311+G(2d,p) basis
structures is the orientation of the hydrogen proR and proS.
In conformer a, the hydrogen proR is in the same direction
as the carbonyl group, while in the conformer b this occurs
with the proS hydrogen.
Considering the topological theory of atoms in
molecules and using the AIMAll software, the charges41
of the oxygen, hydrogens proR and proS were calculated
and are summarized in Table 3.
Atom
Compound
Oxygen
−1.198
−1.184
−1.186
HproR
HproS
3b
3f
+0.101
+0.104
+0.104
+0.031
+0.030
+0.039
3h
Table 3. AIM charges of the selected conformers of 3b calculated at the
mPW1B95/6-311+G(2d,p) level of theory
downfield shift and electronic charge deficiency generated
by dispersion forces.42 The same analysis was done for
structures 3f and 3h, where the same phenomenon was
observed. Electronic delocalization index DI(A,B), an
average number of electrons delocalized between atoms A
and B, is an additional information that can be extracted
from AIM calculations.43 Table 5 shows the delocalization
index between the oxygen and the analyzed hydrogens.
These values are higher when the hydrogen is closer to the
carbonyl group, showing that the difference in chemical
shifts of protons proR and proS may be attributed to this
interaction.
Proton
Conformer
Oxygen
HproR
HproS
a
−1.187584
−1.190171
+0.107024
+0.021578
+0.027274
+0.086625
b
These results show that when the hydrogen is near to
the oxygen of the carbonyl group a charge deficiency is
observed. To explain the chemical shifts observed, the
charge of the considered atoms was calculated considering
these two conformers as in equation 2:
Table 5. Electron delocalization index calculated with AIM at the
mPW1B95/6-311+G(2d,p) level of theory
q(i) = χaq(i)a + χbq(i)b
(2)
Compound
DI(O,HproR
0.052525
0.054580
0.055304
)
DI(O,HproS
0.007972
0.010253
0.009755
)
where i represents the atom of interest, χ the conformational
population of each conformer and q(i)x is the charge of i in
the conformer x. Results of charges are shown in Table 4.
It can be observed that the charge of the atoms is defined
by the most important conformer a as expected by the
energy values.
3b
3f
3h
DI: delocalization index.
Conclusions
These differences in the charges can be explained
by suggesting the existence of an interaction between
the hydrogen proR in a and proS in conformer b with
oxygen in the carbonyl group of the molecule promoting
It has been shown that the use of FeCl3/Al2O3 in MeOH
in this reaction is an environmentally benign reaction media.
This is a new approach that meet with the requirements of

Vol. 00, No. 00, 2018
Monreal et al.
7
sustainable chemistry. The remarkable advantages of this
method are simple experiments, mild reaction conditions,
excellent yields and catalyst recovery. In addition, this
catalyst is highly recommended to be used in the synthesis of
quinazolinones. The computational analysis of the chemical
shift of the diasterotopic hydrogens indicates that the main
cause of the large difference between these two hydrogens
were the interaction of these hydrogens with oxygen atom.
The X-ray structures show that when the distance of the
C−O bond is smaller, a greater difference in ppm between
the diasterotopic hydrogens is present. The dihedral angle
(O−C−N−C) is another factor that affects the difference of
the chemical shift of the diasterotopic hydrogens
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Supplementary Information
Supplementary information (spectroscopic data, 1H and
13C NMR spectra and mass spectra (EI)) is available free
of charge at http://jbcs.sbq.org.br as PDF file.
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We gratefully acknowledge the support for this
project by Consejo Nacional de Ciencia y Tecnología
(CONACyT, grant No. 242823) and for graduate scholarship
(No. 221455), also acknowledge Tecnológico Nacional de
México for support this project (Clave 5871.16-P).
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Submitted: May 30, 2018
Published online: August 21, 2018
This is an open-access article distributed under the terms of the Creative Commons Attribution License.