The synthesis of 2,3-dihydroquinazoline-4(1H)-one and dihydroisoindolo[2,1-a]quinazoline-5,11-dione derivatives in the presence of imidazolium ionic liquid sulfonic acid functionalized SBA-15: A novel feature of SBA-15

Article abstract of DOI:10.24820/ark.5550190.p010.448

Imidazole-based ionic liquid-supported on SBA-15 (ImIL-Sul-SBA-15) as a novel heterogeneous catalyst was designed, synthesized and characterized by FT-IR, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and Brunauer-Emmett-Teller (BET) analysis. This novel nano structure was used for the synthesis of various 2,3-dihydroquinazoline-4(1H)-one and dihydroisoindolo[2,1-A]quinazoline-5,11-dione derivatives via three-component reaction between isatoic anhydride, amines and aromatic aldehydes at 50 °C in ethanol and water mixture as solvent. We found the synthetic imidazolium ionic liquid sulfonic acid functionalized SBA-15 as a convenient catalyst for this methodology. The catalyst performs the reaction in mild reaction conditions, and can easily be separated from the reaction mixture by simple filtration, with no need to tedious purification steps. Formula parented.

Full text of DOI:10.24820/ark.5550190.p010.448

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The synthesis of 2,3-dihydroquinazoline-4(1H)-one and dihydroisoindolo[2,1-
a]quinazoline-5,11-dione derivatives in the presence of imidazolium ionic liquid
sulfonic acid functionalized SBA-15: a novel feature of SBA-15
Sepideh Abbasiana, Hassan Kabirifard*a and Mohammad Mahdavib
aDepartment of Chemistry, North Tehran Branch, Islamic Azad University, Tehran, Iran
b Endocrinology & Metabolism Research Institute,Tehran University of Medical, Iran
Email: h_kabirifard@iau-tnb.ac.ir
Received 12-20-2017
Accepted 02-27-2018
Published on line 05-18-2018
Abstract
Imidazole-based ionic liquid-supported on SBA-15 (ImIL-Sul-SBA-15) as a novel heterogeneous catalyst was
designed, synthesized and characterized by FT-IR, scanning electron microscopy (SEM), transmission electron
microscopy (TEM), and Brunauer-Emmett-Teller (BET) analysis. This novel nano structure was used for the
synthesis of various 2,3-dihydroquinazoline-4(1H)-one and dihydroisoindolo[2,1-a]quinazoline-5,11-dione
derivatives via three-component reaction between isatoic anhydride, amines and aromatic aldehydes at 50 °C
in ethanol and water mixture as solvent. We found the synthetic imidazolium ionic liquid sulfonic acid
functionalized SBA-15 as a convenient catalyst for this methodology. The catalyst performs the reaction in
mild reaction conditions, and can easily be separated from the reaction mixture by simple filtration, with no
need to tedious purification steps.
OHC
O
R
N
X
O
N
H
ImIL-Sul-SBA-15 (20 mol%)
H2O:EtOH (1:1), 50 oC, 1 h
O
X
RNH2
+
OHC
O
O
N
H
R
HOOC
N
X
N
O
X
Keywords: Isatoic anhydride, Imidazolium ionic liquid sulfonic acid functionalized SBA-15, Three-component
reaction, 2,3-Dihydroquinazolin-4(1H)-one, Dihydroisoindolo[2,1-a]quinazoline-5,11-dione
DOI: https://doi.org/10.24820/ark.5550190.p010.448
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Introduction
The catalysts are notable moiety of very synthetic reactions due to their properties such as decreasing of
reaction time and temperature. In addition, the catalytic processes are ecologically sustainable because the
catalysts prevent in environmental pollution. In the last decade, several developments were proceeded to
design, synthesis and application examination of catalysts for various chemical and pharmaceutical synthetic
processes. The heterogeneous catalysts easily separate and recover from reaction mixture. However, these
catalysts must have many active sites, good selectivity, recyclability, reusability, and high stability. The
efficiency of solid catalysts is increased by great pores with numerous active sites.1-3
Mesoporous silica nanoparticles are important due to their porous structure and high surface area. These
materials have been used as support for catalysts because of their unique properties.4-6
2,3-Dihydroquinazolin-4(1H)-ones (DHQZs) are important classes of heterocycles and have the broad range of
pharmacological and biological properties. These compounds exhibit antiviral,7 anti-inflamatory,8,9
antihistamine,10 cytotoxic,11 antibiotic,12 analgesic,13 anticonvulsant,13 antitumor,11,13 vasodilatory,14
antidefibrillatory,15 antihypertensive activities.16
According to these wide ranges of pharmacological activities, several synthetic routes have been reported
for the preparation of DHQZs. The important method for the synthesis of DHQZs involves the condensation of
anthranilamide with aldehydes or ketones using several catalysts such as montmorillonite K-10,17 gallium(III)
triflate,18 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim]BF4),19 MCM-41-SO3H,20 Al/Al2O3
nanocatalyst,21 PEG-OSO3H,22 silica sulfuric acid,23 KAl(SO4)2.12H2O,24 cyanuric chloride,25 zinc(II)
perfluorooctanoate [Zn(PFO)2],26 and molecular iodine.27 In addition, the use of three-component reaction
between isatoic anhydride, amines and aromatic aldehydes catalyzed by Lewis and Brønsted acid catalysts, is
an applicable route for the synthesis of DHQZs.28,29 However, most of these methods proceeded by the use of
complex and expensive catalysts or media, and have notable disadvantages such as harsh reaction conditions,
long reaction times, and low yields. Therefore, the development of a novel and efficient approach to produce
DHQZs using efficient catalysts is still desirable. Regarding the advantages of mesoporous silica nanoparticles,
in this paper we repost a catalyst based on functionalized SBA-15 by imidazolium ionic liquid sulfonic acid for
the synthesis of 2,3-dihydroquinazoline-4(1H)-ones (4a-d) and dihydroisoindolo[2,1-a]quinazoline-5,11-diones
(6a-j) (Scheme 1).
OHC
O
3a-c
R
N
X
N
H
4a-d
O
X
ImIL-Sul-SBA-15 (20 mol%)
O
RNH2
+
H2O:EtOH (1:1), 50 oC, 1 h OHC
O
N
H
O
N
5a,b
2a-f
R
1
HOOC
N
X
6a-j
O
X
Scheme 1. The synthesis of 2,3-dihydroquinazoline-4(1H)-ones (4) and dihydroisoindolo[2,1-a]quinazoline-
5,11-diones (6) in the presence of ImIL-Sul-SBA-15.
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Results and Discussion
The catalyst was prepared by the synthesis and functionalization of SBA-15 mesoporous silica nanoparticles.
SBA-15 mesoporous silica was prepared via solvothermal reaction of tetraethyl orthosilicate in acidic
conditions. After the preparation of SBA-15 mesoporous silica, the nanoparticles were functionalized by
sulfonic acid, and finally were treated by methyl imidazole. The preparation steps of the catalyst can be seen
in Scheme 2.
Scheme 2. The preparation steps of the catalyst.
FT-IR spectroscopy was used for the determination of the functionalities of the catalyst (Figure 1). A sharp
absorbance at 1100 cm-1 can be correlated to the Si-O vibration bands. A broad peak at 3340 cm-1 can be
correlated to hydroxyl groups of the catalyst. S=O vibrations can be observed as a vibration band at 1190 cm-1.
Imidazole vibrations can be seen at 1447 cm-1.
Figure 1. FT-IR spectra of alkyl-sulfonic supported acid SBA-15 (a) and ionic liquid supported SBA-15 (b).
The catalyst was characterized by various methods. TEM and SEM microscopy were applied for
determining the microstructure, particle size and morphology of the catalyst. The images for TEM and SEM
can be seen in Figure 2 respectively. The ordered porous structure of ImIL-Sul-SBA-15 catalyst can clearly be
observed in TEM images. In SEM images, the rod like morphology of ImIL-Sul-SBA-15 can be seen.
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Figure 2. TEM (left) and SEM (right) images of the catalyst.
For the determination of the pore size and the size dispersity of the pores of the catalyst, nitrogen
adsorption desorption method was used. The results, which are shown in Figure 3, show the pore size of the
catalyst to be 85 nm. As can be seen , the pore size distribution of the catalyst is narrow.
Figure 3. Pore size analysis of the catalyst.
The thermal stability of the catalyst was investigated by TGA method. The TGA results can be seen in
Figure 4. A weight loss has happened in about 100 °C, which can be related to the evaporation of the water. In
230-250 °C a sharp weight loss can be observed, which can be correlated to the thermal decomposition of the
organic functionalities. It can be observed in TGA results that, the catalyst is stable till 230 °C and no thermal
decomposition has been observed in lower temperatures. A comparison between SBA-15 and ImIL-Sul-SBA-15
in Figure 4 shows about 10% of functionalization by weight.
Figure 4. TGA analysis of the catalyst.
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The activity of our catalyst was examined in three-component reactions between isatoic anhydride,
amines and aromatic aldehydes for the synthesis of various 2,3-dihydroquinazolin-4(1H)-one (4) and
dihydroisoindolo[2,1-a]quinazoline-5,11-dione (6) derivatives. So, the reaction between isatoic anhydride 1,
benzylamine 2a and 4-chlorobenzaldehyde 3a, as a model reaction, was investigated in various reaction
conditions.
As shown in Table 1, no product was detected when the reaction occurred at room temperature in the
presence of 10 mol% of the ImIL-Sul-SBA-15 in water after 10 h (entry 1). The DHQZ 4 was generated in low
yield (33%) by increasing of reaction temperature to 40 °C after 1 h (entry 2). Although, the increasing of
reaction temperature to 50 °C led to increasing of the yield of product to 38% (entry 3), more increasing of
reaction temperature did not effect on the yield of product (entry 4). Continuously, the effect of amount of
ImIL-Sul-SBA-15 was tested and the desired product was generated in 67% yield in the presence of 20 mol% of
our catalyst (entry 6). Performing the reaction with higher amounts of catalyst did not lead to higher product
yields (entries 7 and 8). Then, we examined the reaction in various solvents (entries 9–16), and surprisingly, it
was found that the best yield of product was achieved in the mixture of EtOH:H2O (1:1) and EtOH although the
reaction led to acceptable yields in DMF and THF (entry 12,13).
Table 1. Optimization of reaction conditions for the synthesis of DHQZ 4a in the presence of ImIL-Sul-SBA-15a
Ph
O
O
O
O
N
H
ImIL-Sul-SBA-15 (Amount)
Solvent
PhCH2NH2
+
+
Cl
O
N
H
N
H
4a
3a
2a
1
Cl
Entry
1
2
3
4
5
6
7
8
Amount (mol%)
Solvent
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
CH2Cl2
CHCl3
DMSO
DMF
THF
Temp. (°C)
r.t
Time (h)
Yieldb (%)
0
10
10
10
10
15
20
30
50
20
20
20
20
20
10
10
20
10
1
1
1
1
1
1
1
10
10
10
10
10
10
1
40
50
60
50
50
50
50
50
50
50
50
50
50
50
50
33
38
38
54
67
67
65
57
55
60
67
58
50
88
90
9
10
11
12
13
14
15
16
toluene
EtOH
EtOH:H2O (1:1)
1
a
Reaction conditions: use of isatoic anhydride 1 (1.0 mmol), benzylamine 2a (1.0 mmol) and 4-chlorobenzaldehyde 3a
(1.0 mmol) and appropriate amount of ImIL-Sul-SBA-15; solvent (3 mL); related temperature; time.b Isolated yield.
To show the generality of this new method, the reactions were performed using various amines 2, and
aromatic aldehydes 3 with isatoic anhydride 1 in the presence of 20 mol% ImIL-Sul-SBA-15 in 3 mL of
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EtOH:H2O (1:1) at 50 °C. The reactions led to produce the corresponding DHQZs 4a-d in 85-93% yields (Table
2). In addition, the reaction between isatoic anhydride 1, amines 2 and 2-carboxyaldehydes 5 was studied
under similar reaction conditions and the corresponding dihydroisoindolo[2,1-a]quinazoline-5,11-diones 6a–j
was generated in 86-95% yields (Table 2). All the reactions reached to completion within 1 h.
Table 2. ImIL-Sul-SBA-15 catalyzed synthesis of 2,3-dihydroquinazoline-4(1H)-ones (4) and
dihydroisoindolo[2,1-a]quinazoline-5,11-diones (6)a
Entry Amine (2); R=
Aldehyde (3 and 5); X= Product (4 and 6)
Yieldb (%)
90
1
2
2a; PhCH2
3a; 4-Cl
4a
4b
4c
4d
6a
6b
6c
6d
6e
6f
2a; PhCH2
3b; 4-CH3O
3c; 2,3-Cl2
3a; 4-Cl
86
3
2a; PhCH2
85
4
2b; CH2=CHCH2
2a; PhCH2
93
5
5a; H
90
6
2b; CH2=CHCH2
2c; 2-ClC6H4CH2
2d; 2-C4H3OCH2
2e; 2-C5H4NCH2
2f; 4-ClC6H4CH2
2a; PhCH2
5a; H
95
7
5a; H
88
8
5a; H
88
9
5a; H
91
10
11
12
13
5a; H
87
5b; 2,3-(CH3O)2
5b; 2,3-(CH3O)2
5b; 2,3-(CH3O)2
5b; 2,3-(CH3O)2
6g
6h
6i
89
2d; 2-C4H3OCH2
2e; 2-C5H4NCH2
2f; 4-ClC6H4CH2
87
90
14
6j
86
a
All the reactions were carried out using isatoic anhydride 1 (1.0 mmol), amine 2 (1.0 mmol), aromatic aldehyde 3 or 5
(1.0 mmol), and ImIL-Sul-SBA-15 (w/w 20%) in EtOH:H2O (3 mL) at 50 °C. b Isolated yield.
1
The structures of the products 4 and 6 were deduced by IR, H NMR, 13C NMR and some Mass
spectroscopy. All spectroscopic studies are available in supporting information.
We suggest that ImIL-Sul-SBA-15 catalyzes the reaction as a mild Lewis acid. A plausible mechanism for the
formation of isoindolo[2,1-a]quinazoline-5,11-dione derivatives (6) is depicted in Scheme 3. The nucleophilic
attack of amine (2) on the activated carbonyl carbon by ImIL-Sul-SBA-15 of isatoic anhydride (1) obtains 2-
aminobenzamide intermediate. The further nucleophilic attack by the amino group of 2-aminobenzamide on
the carbonyl carbon of 2-formylbenzoic (5) facilitated by ImIL-Sul-SBA-15 generates the Schiff base. Then, the
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intramolecular acylamino group attacks the ImIL-Sul-SBA-15-activated Schiff base to form the quinazoline;
finally, an intramolecular dehydration to give the desired product 6.
IL
O
O
O
NHR
NHR
O
-CO2
H2N
R
+
NH2
O
NH
N
H
2
IL
1
O
H
O
O
O
H
-H2O
5
HO
X
O
O
O
R
R
R
N
N
O
N
-H2O
H
N
H
HO
N
N
HO
IL
O
6
X
X
O
X
IL
Scheme 3. Plausible mechanism for the formation of isoindolo[2,1-a]quinazoline-5,11-diones (6).
After completion of the reaction, the precipitate was separated by filtration. The resulting precipitate is
mixture of desired product and ImIL-Sul-SBA-15. To separate the products from the catalyst, this solid was
washed with EtOH and ImIL-Sul-SBA-15 was remained as solid. A great advantage of this catalyst in this
synthesis is simple separability using filtration, which can easily lead to the facile reusability of the catalyst. To
study the recyclability of the ImIL-Sul-SBA-15, the reused catalyst was employed for another reaction. We
found that, the catalyst could be reused successfully up to 6 times without obvious loss of catalytic activity.
The results are presented in Figure 5.
Figure 5. The recycling studies for ImIL-Sul-SBA-15.
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An advantage of this catalytic system is that, the products are obtained in milder reaction conditions. In a
similar report, the products are obtained in higher temperature and acetic acid is used as solvent, which is
more difficult than the current report.30 The other advantage of this catalytic method is its non-toxic feature.
Metallic species such as gallium(III) triflate have been used as catalyst for the synthesis of quinazolinone
derivatives.18 These species are toxic and harmful for the environment, which limits their use in industries.
Conclusions
In conclusion, we have developed an efficient catalytic approach for the synthesis of various 2,3-dihydroquinazoline-
4(1H)-ones (4) and dihydroisoindolo[2,1-a]quinazoline-5,11-diones (6) via reaction between isatoic anhydride 1, amines
2 and aldehydes 3 or 2-carboxyaldehydes 5 in the presence of ImIL-Sul-SBA-15. The reactions were carried out without
the use of high temperature, and complex, toxic and expensive catalyst and reagents. The recoverability and reusability
of our catalyst, relatively short reaction times and high yield of the products are the other advantages of our protocol.
We believe that the success in this process could open the door to the design of diverse reactions and the generation of
interesting organic compounds in the presence of our synthetic catalyst.
Experimental Section
General. Solvents, reagents and chemicals were obtained from Merck (Germany) and Fluka (Switzerland)
Chemical Companies. Elemental analyses were performed using a Heraeus CHN-O-Rapid analyzer. The IR
spectra were obtained on a Nicolet Magna FT-IR 550 spectrophotometer (potassium bromide disks). Nuclear
magnetic resonance spectra were recorded on a Bruker FT-500 spectrometers at 500 and 125 MHz instrument
using tetramethylsilane (TMS) as internal standard in pure deuterated solvents. Chemical shifts are given in
the δ scale in parts per million (ppm) and singlet (s), doublet (d), triplet (t), multiplet (m) and doublet of
doublets (dd) are recorded. Mass spectra were recorded on an Agilent Technology (HP) mass spectrometer
operating at an ionization potential of 70 eV. Thin layer chromatography was carried out on silica gel 254
analytical sheets obtained from Fluka. Transition electron microscope images were recorded on a Hitachi S-
4160. Thermogravimetric analysis of the samples were recorded by TGA Q50 V6.3 Build 189 instrument. SEM
image was papered by Hitachi S-4160 (Cold Field Emission). BET Quantachrome ChemBET 3000 was applied for
determination pore size analysis.
Synthesis of SBA-15. SBA-15 was prepared according to previously reported method.31 To a 1-L Erlenmeyer
flask were added ethyleneoxide-propyleneoxide-ethyleneoxide (EO-PO–EO) triblock copolymer (18.0 g), DI
water (561 g), and concentrated HCl (99.5 g). This mixture was stirred overnight at room temperature to
dissolve the polymer template. Tetraethyl orthosilicate TEOS (39.8 g) was added to the solution and stirred for
5 min, followed by stirring at 35ꢀ°C for 20 h. A static treatment for 24 h at 80ꢀ°C was used to swell the pores.
The mixture was decanted to remove most of the solution, and the white solid was filtered with 3 L of DI
water, recovered, and dried at 60ꢀ°C for 24 h. The white powder was calcined to remove the polymer template
using the following temperature profile: (1) heating to 200ꢀ°C at 1.2ꢀ°C/min, (2) holding at 200ꢀ°C for 1 h, (3)
heating to 550ꢀ°C at 1.2ꢀ°C/min, (4) holding at 550ꢀ°C for 6 h, and (5) cooling to 200ꢀ°C at 1.2ꢀ°C/min.
Preparation of supported alkyl-sulfonic acid. This product was prepared according to modified method,
reported by Ziarani et al.31 To a solution of 1 g of MPTMS in 10 mL of ethanol and 10 mL of water was added
250 mg of SBA-15. The mixture was sonicated for 15 min and refluxed overnight. The SBA-15 supported thiols
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(SBA-15-SH) were recovered magnetically and washed three times with 20 mL of water. The recovered SBA-
15-SH was oxidized by reaction with 10 mL of 30% hydrogen peroxide in 10 mL of water and 10 mL of
methanol overnight at room temperature. The product was recovered magnetically, washed three times with
20 mL of water, and reacidified with 10 mL of 1 M H2SO4. The sulfonic acid-modified SBA-15 (SBA-15-SO3H)
were washed three times with water and dried under vacuum at room temperature overnight.
Synthesis of ionic liquid supported SBA-15. Supported imidazole ionic liquid catalyst was synthesized by the
reaction of 1-methylimidazole and acid-modified SBA-15, by a procedure similar to Yarie et al. reported
method.32 To do this, 1-methylimidazole (100 mg, 1.2 mmol) and acid-modified SBA-15 (250 mg) were mixed
together in a round bottom flask containing 50 mL of toluene and stirred at 80 °C for 72 h. After that time, the
reaction mixture was washed by diethyl ether (3×10 mL) to remove the unreacted compounds. The product
was obtained as a white solid after drying under vacuum for 12 h.
General procedure for the preparation of 2,3-dihydroquinazoline-4(1H)-ones (4a-d) and
dihydroisoindolo[2,1-a]quinazoline-5,11-diones (6a-j). A solution of isatoic anhydride (1 mmol), amines (1
mmol), aldehydes (1 mmol), and ImIL-Sul-SBA-15 (20 mol%) in EtOH:H2O (1:1, 3 mL) was stirred at 50 °C. Upon
completion of the reaction, monitored by TLC, the precipitate was separated by filtration. The precipitate is
mixture of desired product and ImIL-Sul-SBA-15. The ImIL-Sul-SBA-15 was recovered by filtration with EtOH as
precipitate. Then, the solvent of filtrate was evaporated to give crude product which was then purified by
recrystallization from EtOH:H2O (1:1).
ᴼ
4.5.1 3-Benzyl-2-(4-chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (4a). White solid; mp 175-177 C (Ref.33
122-124 °C). IR (KBr): 3279, 1635, 1518, 1310, 1295 cm-1; 1H NMR (CDCl3):  3.68 (1H, d, 2J 15.6 Hz, CH), 5.59
(1H, d, 2J 15.6 Hz, CH), 5.60 (1H, s, CH), 6.53 (1H, d, 3J 8.0 Hz, H-Ar), 6.88 (1H, t, 3J 7.6 Hz, H-Ar), 7.21-7.30 (10H,
m, H-Ar), 8.02 (1H, d, 3J 7.6 Hz, H-Ar), NH proton is missing in spectrum; 13C NMR (CDCl3):  46.92 (CH2), 70.32
(CH), 114.44, 115.63, 119.40, 126.6, 127.53, 127.92, 128.65, 128.76, 129.09, 133.76, 135.11, 136.47, 137.85,
144.83 (18C, 3Ar), 163.11 (C=O) ppm.
ᴼ
4.5.2 3-benzyl-2-(4-methoxy)-2,3-dihydroquinazolin-4(1H)-one (4b). White solid; mp 119-121 C. IR (KBr):
1
2
3358, 3296, 1633, 1610, 1307, 1257 cm-1; H NMR (CDCl3):  = 3.66 (1H, d, J 15.4 Hz, CH), 3.80 (3H, s, OCH3),
4.60 (1H, br s, NH), 5.55 (1H, d, 2J 15.4 Hz, CH), 5.60 (1H, s, CH), 6.52 (1H, d, 3J 8.0 Hz, H-Ar), 6.83 (2H, d, 3J 8.6
Hz, H-Ar), 6.86-7.36 (9H, m, H-Ar), 8.03 (1H, d, J 7.7 Hz, H-Ar); 13C NMR (CDCl3):  = 46.69 (CH2), 70.79 (CH),
3
114.15, 115.67, 119.14, 127.32, 127.81, 127.95, 128.04, 128.52, 128.79, 131.29, 132.46, 136.84, 137.90,
145.23 (18C, 3Ar), 163.27 (C=O) ppm. EI-MS: m/z (%) = 344 (24), 253 (100), 237 (96), 210 (26), 91 (93), 77 (9).
Anal. Calcd for C22H20N2O2 (344.41): C, 76.72%; H, 5.85%; N, 8.13%; found: C, 76.39%; H, 5.61%; N, 7.86%.
ᴼ
4.5.3 3-benzyl-2-(2,3-dichlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (4c). White solid; mp 209-211 C
1
2
(Ref.34 206-208 °C). IR (KBr): 3277, 1628, 1235, 1171 cm-1; H NMR (CDCl3):  3.64 (1H, d, J 15.2 Hz, CH),
5.00 (1H, br s, NH), 5.71 (1H, d, 2J 15.2 Hz, CH), 6.00 (1H, s, CH), 6.49 (1H, d, 3J 8.0 Hz, H-Ar), 6.85 (1H, t, 3J 7.6
Hz, H-Ar), 7.12-7.30 (9H, m, H-Ar), 8.01 (1H, d, J 8.1 Hz, H-Ar); 13C NMR (CDCl3):  47.65 (CH2), 67.57 (CH),
3
114.66, 115.45, 119.45, 125.28, 127.78, 127.79, 128.07, 128.67, 128.77, 130.21, 130.78, 133.83, 134.08,
136.20, 138.38, 144.15 (18C, 3Ar), 163.42 (C=O) ppm.
4.5.4 3-Allyl-2-(4-chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (4d). White solid; mp 168-170 ᴼC. IR
(KBr): = 3298, 1631, 1510, 1306, 1235 cm-1; 1H NMR (CDCl3):  = 3.23 (1H, dd, 2J 15.7 Hz, 3J 7.4 Hz, CH), 4.84
2
3
3
3
(1H, dd, J 15.7 Hz, J 7.4 Hz, CH), 5.17 (1H, d, Jcis 10.7 Hz, =CH), 5.20 (1H, d, Jtrans 17.5 Hz, =CH), 5.73 (1H, s,
CH), 5.79 (1H, m, =CH), 6.54 (1H, d, 3J 8.1 Hz, H-Ar), 6.87 (1H, t, 3J 7.6 Hz, H-Ar), 7.31 (5H, m, H-Ar), 7.97 (1H, d,
3J 7.5 Hz, H-Ar), NH proton is missing in spectrum; 13C NMR (CDCl3):  = 46.25 (CH2), 70.51 (CH), 114.40,
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115.89, 117.92 (=CH2), 119.51, 127.95, 128.65, 129.14, 132.43 (=CH), 133.66, 135.16, 137.97, 144.76 (12C,
2Ar), 162.76 (C=O) ppm. EI-MS: m/z (%) = 300 (M·++2, 7), 298 (M·+, 11), 257 (22), 187 (100), 147 (24), 119 (15),
92 (11). Anal. Calcd for C17H15ClN2O (298.77): C, 68.34%; H, 5.06%; N, 9.38%; found: C, 68.61%; H, 4.82%; N,
9.02%.
ᴼ
4.5.5 6-Benzyl-6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione (6a). White solid; mp 140-142 C (Ref.35
148-150 °C). IR (KBr): 3028, 1721, 1654, 1601, 1486, 1465 cm-1; 1H NMR (CDCl3):  = 4.62 (1H, d, 2J 16.7 Hz,
2
CH), 5.53 (1H, d, J 16.7 Hz, CH), 6.37 (1H, s, CH), 7.21-8.24 (13H, m, H-Ar); 13C NMR (CDCl3):  46.61 (CH2),
70.65 (CH), 120.19, 120.29, 124.97, 125.31, 125.40, 126.25, 127.25, 129.03, 129.46, 130.59, 132.52, 132.68,
133.71, 136.14, 136.89, 137.69 (18C, 3Ar), 164.08, 164.84 (2C=O) ppm.
4.5.6 6-Allyl-6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione (6b). White solid; mp 124-126 ᴼC. IR (KBr):
3084, 2930, 1713, 1648, 1488, 1469 cm-1; 1H NMR (CDCl3):  = 4.09 (1H, dd, 2J 16.6 Hz, 3J 4.6 Hz, CH), 4.81 (1H,
d, 2J 16.6 Hz, CH), 5.22 (1H, d, 3Jtrans 19.6 Hz, =CH), 5.27 (1H, d, 3Jcis 11.8 Hz, =CH), 5.91 (1H, m, =CH), 6.32 (1H, s,
CH), 7.33-8.17 (8H, m, H-Ar); 13C NMR (CDCl3):  45.10 (CH2), 70.47 (CH), 116.79 (=CH2), 120.06, 120.18,
125.04, 125.25, 129.24, 130.63, 132.63 (=CH), 132.71, 132.80, 133.58, 136.79, 137.86 (12C, 2Ar), 163.65,
164.74 (2C=O) ppm. EI-MS: m/z (%) = 290 (100), 261 (45), 233 (50), 218 (18), 116 (13), 89 (18), 63 (14). Anal.
Calcd for C18H14N2O2 (290.32): C, 74.47%; H, 4.86%; N, 9.65%; found: C, 74.11%; H, 5.18%; N, 9.37%.
4.5.7 6-(2-Chlorobenzyl)-6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione (6c). White solid; mp 180-182
2
ᴼC (Ref.36 185-188 °C). IR (KBr): 1708, 1687, 1601, 1491 cm-1; 1H NMR (CDCl3):  5.04 (1H, d, J 17.5 Hz, CH),
2
5.27 (1H, d, J 17.5 Hz, CH), 6.37 (1H, s, CH), 7.05-8.23 (12H, m, H-Ar); 13C NMR (CDCl3):  44.72 (CH2), 70.66
(CH), 120.0, 120.3, 124.8, 124.9, 125.4, 126.8, 127.2, 128.4, 129.5, 129.8, 130.6, 132.1, 132.4, 132.7, 133.6,
133.9, 137.0, 137.4 (18C, 3Ar), 164.17, 164.92 (2C=O) ppm.
4.5.8 6-(Furan-2-ylmethyl)-6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione (6d). White solid; mp 173-175
1
2
ᴼC (Ref.37 175-176 °C). IR (KBr): 1722, 1668, 1602, 1489 cm-1; H NMR (DMSO-d6):  4.77 (1H, d, J 16.8 Hz,
CH), 5.12 (1H, d, 2J 16.8 Hz, CH), 6.15 (1H, d, 3J 3.0 Hz, =CHfuran), 6.33 (1H, t, 3J 3.0 Hz, =CHfuran), 6.63 (1H, s, CH),
7.40 (1H, t, 3J 7.5 Hz, H-Ar), 7.53 (1H, t, 3J 3.0 Hz, =CHfuran), 7.70-7.93 (5H, m, H-Ar), 8.03 (2H, d, 3J 8.1 Hz, H-Ar);
13C NMR (DMSO-d6):  45.00 (CH2), 70.20 (CH), 107.38 (C4′), 110.53 (C3′), 119.87, 119.93, 121.42, 124.23,
125.06, 126.07, 128.59, 130.65, 133.08, 133.57, 136.63, 138.10 (12C, 2Ar), 142.33 (C5′), 150.41 (C2′), 162.98,
164.30 (2C=O) ppm.
4.5.9 6,6a-Dihydro-6-(pyridin-2-ylmethyl)isoindolo[2,1-a]quinazoline-5,11-dione (6e). White solid; mp 215-
217 ᴼC (Ref.36 212-214 °C). IR (KBr): 1722, 1660, 1597 cm-1; 1H NMR (DMSO-d6):  4.90 (1H, d, 2J 17.3 Hz, CH),
5.26 (1H, d, 2J 17.3 Hz, CH), 6.81 (1H, s, CH), 7.23-8.48 (12H, m, H-Ar), 13C NMR (DMSO-d6):  47.48 (CH2), 70.65
(CH), 119.88, 119.93, 121.20, 122.19, 124.13, 125.01, 125.89, 128.60, 130.49, 131.91, 132.86, 133.52, 136.79,
136.88, 138.10, 149.05, 156.70 (17C, 2Ar and pyridine), 163.29, 164.31 (2C=O) ppm.
4.5.10 6-(4-Chlorobenzyl)-6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione (6f). White solid; mp 174-176
1
2
ᴼC (Ref.35 178-181 °C). IR (KBr): 1718, 1662, 1605, 1492 cm-1; H NMR (DMSO-d6):  5.02 (1H, d, J 17.2 Hz,
CH), 5.09 (1H, d, 2J 17.2 Hz, CH), 6.71 (1H, s, CH), 7.08 (2H, d, J 8.4 Hz, H-Ar), 7.24 (2H, t, 3J 8.4 Hz, H-Ar), 7.42
3
(1H, t, J 7.7 Hz, H-Ar), 7.60-7.86 (5H, m, H-Ar), 8.05 (2H, d, J 8.7, H-Ar); 13C NMR (DMSO-d6):  45.09 (CH2),
70.21 (CH), 119.96, 124.09, 125.10, 126.08, 127.83, 128.25, 128.62, 130.53, 131.08, 131.68, 132.91, 133.51,
136.51, 136.66, 137.91 (18C, 3Ar), 163.33, 164.29 (2C=O) ppm.
3
3
4.5.11 6-Benzyl-6,6a-dihydro-9,10-dimethoxyisoindolo[2,1-a]quinazoline-5,11-dione (6g). White solid; mp
ᴼ
1
206-208 C (Ref.36 197-200 °C). IR (KBr): 1710, 1656, 1602, 1492 cm-1; H NMR (DMSO-d6):  3.81 (3H, s,
OCH3), 3.86 (3H, s, OCH3), 4.90 (1H, d, 2J 16.9 Hz, CH), 5.06 (1H, d, 2J 16.9 Hz, CH), 6.54 (1H, s, CH), 7.07 (2H, d,
3J 7.7 Hz, H-Ar), 7.16 (1H, t, J 7.1 Hz, H-Ar), 7.23-7.30 (6H, m, H-Ar), 8.00 (1H, d, J 8.2, H-Ar), 8.04 (1H, d, J
3
3
3
7.8, H-Ar); 13C NMR (DMSO-d6):  45.54 (CH2), 56.33, 61.70 (2OCH3), 69.07 (CH), 117.27, 120.14, 120.21,
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121.54, 123.77, 124.98, 125.97, 126.59, 128.40, 128.59, 130.25, 133.30, 136.76, 137.29, 146.94, 153.66 (18C,
3Ar), 162.46, 163.16 (2C=O) ppm.
4.6.12 6-(Furan-2-ylmethyl)-6,6a-dihydro-9,10-dimethoxyisoindolo[2,1-a]quinazoline-5,11-dione (6h). White
ᴼ
1
solid; mp 179-181 C (Ref.36 181-183 °C). IR (KBr): 1731, 1660, 1601 cm-1; H NMR (DMSO-d6):  3.88 (3H, s,
2
2
3
OCH3), 3.91 (3H, s, OCH3), 4.66 (1H, d, J 16.8 Hz, CH), 5.08 (1H, d, J 16.8 Hz, CH), 6.17 (1H, d, J 3.0 Hz,
=CHfuran), 6.36 (1H, dd, J 3.0, 1.9 Hz, =CHfuran), 6.46 (1H, s, CH), 7.37 (1H, t, J 7.3 Hz, H-Ar), 7.43 (1H, d, J 8.4
Hz, H-Ar), 7.49 (1H, d, J 8.4 Hz, H-Ar), 7.56 (1H, d, J 1.9 Hz, =CHfuran), 7.69-8.00 (3H, m, H-Ar); 13C NMR
(DMSO-d6):  47.20 (CH2), 56.37, 61.74 (2OCH3), 69.06 (CH), 107.32 (C4′), 110.57 (C3′), 117.40, 120.02, 120.18,
121.59, 123.81, 124.95, 128.51, 130.31, 133.37, 136.72, 147.08, 153.81 (12C, 2Ar), 142.32 (C5′), 150.48 (C2′),
162.47, 162.91 (2C=O) ppm.
3
3
3
3
3
4.5.13
6,6a-Dihydro-9,10-dimethoxy-6-(pyridin-2-ylmethyl)isoindolo[2,1-a]quinazoline-5,11-dione (6i).
White solid; mp 214-216 ᴼC (Ref.36 210-212 °C). IR (KBr): 1726, 1659, 1603, 1590 cm-1; 1H NMR (DMSO-d6): 
3.82 (3H, s, OCH3), 3.90 (3H, s, OCH3), 4.83 (1H, d, 2J 17.2 Hz, CH), 5.22 (1H, d, 2J 17.2 Hz, CH), 6.64 (1H, s, CH),
7.12-8.50 (10H, m, H-Ar); 13C NMR (DMSO-d6):  47.24 (CH2), 56.33, 61.72 (2OCH3), 69.49 (CH), 117.24, 120.14,
121.29, 121.43, 122.21, 123.92, 124.91, 128.52, 130.35, 133.35, 136.88, 136.99, 146.98, 148.96, 153.69,
156.74 (17C, 2Ar and pyridine), 162.49, 163.23 (2C=O) ppm.
4.5.14 6-(4-Chlorobenzyl)-6,6a-dihydro-9,10-dimethoxyisoindolo[2,1-a]quinazoline-5,11-dione (6j). White
ᴼ
1
solid; mp 185-187 C (Ref.36 180-182 °C). IR (KBr): 1726, 1658, 1606, 1491 cm-1; H NMR (DMSO-d6):  3.82
3
(3H, s, OCH3), 3.87 (3H, s, OCH3), 4.97 (2H, br s, CH2), 6.53 (1H, s, CH), 7.08 (2H, d, J 7.7 Hz, H-Ar), 7.26-8.04
(8H, m, H-Ar); 13C NMR (DMSO-d6):  45.00 (CH2), 56.35, 61.70 (2OCH3), 69.07 (CH), 117.32, 120.16, 120.21,
121.62, 123.72, 124.98, 127.92, 128.27, 128.57, 130.20, 131.10, 133.32, 136.56, 136.77, 146.97, 153.69 (18C,
3Ar), 162.44, 163.25 (2C=O) ppm.
Supplementary Material
Copies of 1H, 13C NMR and some Mass spectra of compounds 4a-d and 6a-j are provided in the supplementary
material file available on the Publisher’s web site.
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