Facile, catalyst-free, microwave-assisted access toward the synthesis of 2-aryl/alkyl-3-(1H-benzo[d]imidazol-2-yl)-2, 3-dihydroquinazolin-4(1H)-ones

Article abstract of DOI:10.1080/00397911.2016.1277761

An efficient, catalyst-free, microwave-assisted approach has been developed for the synthesis of 2-aryl/alkyl-3-(1H-benzo[d]imidazol-2-yl)-2,3-dihydroquinazolin-4(1H)-one derivatives by condensing 2-aminobenzamides with various aliphatic, aromatic, and heterocyclic aldehydes. This catalyst-free approach exhibited good functional group compatibility and produced the desired products in good to excellent yields in just 10–20 min. This approach can be seen as a better alternative of the metal-catalyzed protocols used for the synthesis of this class of compounds. The formation of desired compound has also been confirmed by X-ray analysis.

Full text of DOI:10.1080/00397911.2016.1277761

A Facile, Catalyst-Free, Microwave-Assisted Access towards the Synthesis of 2-
Aryl/Alkyl-3-(1H-benzo[d]imidazol-2-yl)-2,3-dihydroquinazolin-4(1H)-ones
Prashant Kumar1, Akanksha Matta1,2, Snigdha Singh1, Johan Van der Eycken2,
Christophe Len3,4, Virinder S. Parmar1, Erik V. Van der Eycken5, Brajendra K. Singh1
1Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi, India,
2Laboratory for Organic and Bioorganic Synthesis, Department of Organic Chemistry,
Ghent University, Ghent, Belgium, 3Sorbonne Universités, Université de Technologie de
Compiègne (UTC), Ecole Supérieure de Chimie Organique et Minérale (ESCOM0),
Compiègne Cedex, France, 4Department of Chemistry, University of Hull, Hull HU6
7RX, UK, 5Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC),
Department of Chemistry, University of Leuven (KU Leuven), Leuven, Belgium
Corresponding-Author to Dr. Brajendra Kumar Singh. E-mail:
singhbk@chemistry.du.ac.in
Abstract
An efficient, catalyst free, microwave assisted approach has been developed for the
synthesis of 2-aryl/alkyl-3-(1H-benzo[d]imidazol-2-yl)-2,3-dihydroquinazolin-4(1H)-one
derivatives by condensing 2-aminobenzamides with various aliphatic, aromatic and
heterocyclic aldehydes. This catalyst free approach exhibited good functional group
compatibility and produced the desired products in good to excellent yields in just 10-20
minutes. This approach can be seen as a better alternative of the metal catalyzed
protocols used for the synthesis of this class of compounds. The formation of desired
compound has also been confirmed by X-ray analysis.
GRAPHICAL ABSTRACT
1

KEYWORDS: Catalyst free; Microwave irradiation; Substrate scope; Short reaction
time; 2,3-dihydroquinazolinone
INTRODUCTION
The modern era of synthetic organic chemistry has witnessed a rapid expansion in the
development of efficient protocols that involve the use of transition metal catalysts or
Lewis acid catalysts for the generation of industrially significant heterocyclic
molecules.1-4 Although, different catalytic approaches have shown high efficiency in
providing rapid access to a large number of heterocyclic compounds, however from an
economic and chemical standpoint, they present some serious problems such as high cost,
contamination of the product, waste production, involvement of harsh reaction
conditions, etc. Therefore, the exploration of novel, catalyst free pathways is presently an
issue of significance in order to expand the frontiers of heterocyclic chemistry.
The quinazolinone structure is a prevalent synthetic as well as natural scaffold that has
been extensively employed as drug like template in medicinal chemistry.5-11 Amongst the
leading derivatives of quinazolinones, 2,3-dihydroquinazolin-4(1H)-ones in particular
have become the most attractive targets in organic synthesis, as they are an integral part
2

of many bioactive molecules that exhibit a broad spectrum of pharmacological properties
(Figure 1)12-15, such as anti-malarial16, anti-cancer17, anti-microbial18, 19, anti-
hypertensive20-23, anti-oxidant24, 25, anti-inflammatory.26-28 They also function as
inhibitors of several key enzymes e.g. dihydrofolate reductase29-31, poly(ADP-
ribose)polymerase32 and human microsomal prostaglandin synthase 1 (mPGES 1).33
Considering the significance of the quinazolinone scaffold, several methods have
been reported for the synthesis of 2-aryl/alkyl-3-(1H-benzo[d]imidazol-2-yl)-2,3-
dihydroquinazolin-4(1H)-ones using 2-aminobenzamides and benzaldehydes as starting
material under the influence of various catalytic systems like cyanuric chloride34, CuI35,
,Poly(VPyPS)-PW36, Co-CNTs37, 2-morpholinoethanesulfonic acid38, indion ina 225H
resin39, Amberlyst-1540, ionic liquid41,42 boehmite-SSA43, boehmite-Si-DSA44, L-proline
nitrate45, NH4Cl46, TiCl4-Zn47, Cellulose-SO3H48 etc, (Scheme 1). Although these
synthetic methodologies lead to the generation of the targeted quinazolinones, however a
number of challenges need to be addressed as they intrinsically suffer from some serious
limitations such as limited substrate scope, employment of a toxic and expensive catalyst
that invariably leads to product contamination, moisture-sensitivity of catalysts make
their use difficult, need for prior synthesis of catalyst which is unfavorable in terms of
both atom economy and requirement of high energy consuming instruments for their
characterization, etc.
The challenges associated with metal catalyzed synthesis of this highly significant
scaffold encouraged us to investigate more expedient methods for the construction of 2,3-
3

dihydroquinazolin-4(1H)-ones. Recently, our group has reported a base-mediated
synthesis of benzimidazo[1,2-a]quinazolines as our first step towards the direction of
catalyst free synthesis.49 While investigating its reaction mechanism, interestingly we
found that 2,3-dihydroquinazolin-4(1H)-ones could be obtained under catalyst free
reaction conditions. Encouraged by this observation and as an extension of our previous
work, we decided to carry out the synthesis of 2,3-disubstituted-2,3-dihydroquinazolin-
4(1H)-one derivatives by condensing 2-aminobenzamides with various aldehydes without
use of any catalyst under microwave irradiation. To the best of our knowledge there is no
report of catalyst free synthesis of 2-aryl/alkyl-2,3-dihydroquinazolin-4(1H)-ones using
2-aminobenzamides and aldehydes as starting materials. The structure of the key
compound was confirmed using X-ray crystal structure analysis.
RESULT AND DISCUSSION
Our investigation started with the condensation of 2-amino-N-(1H-benzo[d]imidazol-2-
yl)benzamide (1a) and 2-chlorobenzaldehyde (2a) in DMF under irradiation with
microwaves at 80 W maximum power for 10 minutes at a ceiling temperature of 130 oC.
To our great satisfaction, the desired product was obtained in 83% yield (Table 1, entry
1). However, drop in the product yield was observed when reaction was prolonged (Table
1, entry 2). When the reaction was performed under conventional heating at 130 oC, the
reaction was completed in 4 hours and the desired product was obtained in 65% yield
(Table 1, entry 3).
4

Encouraged by these outcomes we further screened various solvents like toluene, 1,4-
dioxane, ethanol, acetonitrile and water under the microwave conditions. It was observed
that the aprotic solvents provided better product yields as compare to the protic solvents.
Out of these screened solvents, except water where no product formation was observed
even after irradiation for 30 min (Table 1, entry 8), all solvents yielded the desired
product 3a in relatively moderate to good yields. It was also found that the reaction did
not proceed to completion when it was irradiated in toluene for 30 min (Table 1, entry 4).
Moreover, no product formation was observed when the reaction was performed in the
absence of any solvent (Table 1, entry 9).
Firstly, substrate scope of this newly optimized protocol with a wide range of aliphatic,
heterocyclic and aromatic aldehydes with 2-amino-N-(1H-benzo[d]imidazol-2-
yl)benzamide was explored. All the employed aldehydes reacted efficiently with 2-
amino-N-(1H-benzo[d]imidazol-2-yl)benzamide and furnished the desired products in
good to excellent yields (Table 2).
During the course of this investigation, it was observed that the electronic nature and the
positions of the substituents on the aromatic ring of the benzaldehyde significantly affect
the outcome of the reaction. Benzaldehydes with electron withdrawing group at ortho
position yielded the desired product in lower yields (Table 2, entries 3a and 3b), however
significant decrease in product yield was observed when electron withdrawing group was
present at the para position (Table 2, entries 3g-3i) as compared to the unsubstituted
benzaldehyde (Table 2, entry 3d). Moreover, higher product yield was obtained when
5

electron donating group was present at para position of the benzaldehyde analogues
(Table 2, entries 3e and 3f). Substantially lower yield in case of -NO2 group (Table 2,
entry 3c) may be attributed to strong electron withdrawing nature of -NO2 group.
Nevertheless, aliphatic and heterocyclic aldehydes also furnished the corresponding
products in good yields (Table 2, entries 3n-3r). The structure of compound 3a has been
confirmed by single crystal X-ray analysis (Figure 2). The details of data collection,
structure solution and refinement for compound 3a are listed in Table 3 (see supporting
information).
Substrate scope was further explored with other reaction partner i.e. 2-aminobenzamide.
Various 2-aminobenzamides were allowed to react with benzaldehyde. Much to our
delight, all the employed benzamides resulted in good to excellent product yields (Table
4).
Initially, to examine whether any change in the starting material would cause variation in
the reaction yields, we performed competitive experiments (Scheme 2). When 2-amino-
N-(1H-benzo[d]imidazol-2-yl)benzamides (1) was allowed to react with an equimolar
mixture of p-methoxybenzaldehyde (2f) and p-nitrobenzaldehyde (2i), products 3f and 3i
were obtained in 1:1.4 ratio. Likewise, when equal amount of 2-amino-N-(6-methyl-1H-
benzo[d]imidazol-2-yl)benzamide (4c) and 2-amino-N-(6-chloro-1H-benzo[d]imidazol-2-
yl)benzamide (4d) was subjected to a reaction with benzaldehyde, products 5c and 5d
were obtained in 1:1.1 ratio. These experiments revealed that when the substrates bearing
electron donating group were made to react individually, they provided better yields than
6

substrates bearing electron withdrawing group. However in the mixture, substrates with
electron withdrawing group not only reacted faster, but also resulted in higher yields in
comparison to substrates containing electron donating group.
CONCLUSION
We have developed an efficient catalyst free approach for the synthesis 2-aryl/alkyl-3-
(1H-benzo[d]imidazol-2-yl)-2,3-dihydroquinazolin-4(1H)-one derivatives starting from
2-aminobenzamides and benzaldehydes. This methodology was found to show good
functional group tolerance and a wide range of differently substituted derivatives could
be synthesized in good to excellent yields. Substrate scope and product yields of this
approach are excellent. Further, to evaluate functional group compatibility competitive
experiment was carried out and found that substrates bearing electron withdrawing
groups reacts faster than containing electron releasing groups. This catalyst free approach
can been seen as an attractive and alternative pathway to the previously reported metal-
catalyzed synthesis of this medicinally important class of compounds.
EXPERIMENTAL
General Procedure For The Synthesis Of 3-(1H-Benzo[D]Imidazol-2-Yl)-2-(2-
Chlorophenyl)-2,3-Dihydroquinazolin-4(1H)-One (3a)
A mixture of the N-(2-benzimidazolyl)-2-aminobenzamides (0.79 mmol) and aldehydes
(0.95 mmol) in DMF (2 mL) was taken in a microwave transparent glass vial equipped
with a small magnetic stirring bar, and the vial was tightly sealed with a Teflon crimp cap.
The mixture was then irradiated for the appropriate time at 130 oC and 80 W maximum
7

power. Completion of the reaction was monitored by TLC (20 % ethyl acetate in hexane).
The reaction mixture was then cooled to room temperature and then poured onto crushed
ice. The precipitated crude product was filtered and finally purified by column
chromatography over silica gel using 15% ethyl acetate in hexane to give 3a (129 mg,
83%) as a yellow solid; mp 247-249 oC; Rf = 0.40 (30% EtOAc-Hexane).
It was obtained as light yellow solid having m. p. 247-249 oC in 83% yield. IR (CHCl3)
νmax (cm-1): 3363, 3066, 2925, 1658, 1614, 1527, 1448, 1237, 751. 1H NMR (400 MHz,
CDCl3): δ 11.70 (1H, s), 8.03 (1H, d, J = 8.39Hz), 7.73 (1H, d, J = 3.05 Hz), 7.57-7.55
(2H, m), 7.41-7.39 (1H, m), 7.31 (1H, t, J = 7.63 Hz), 7.20-7.16 (3H, m), 7.13-7.11 (1H,
m), 7.07-7.03 (1H, m), 6.87 (1H, d, J = 7.63 Hz), 6.63 (1H, d, J = 8.39 Hz), 5.71 (1H, s).
13C NMR (100 MHz, CDCl3): δ 163.97, 147.15, 145.13, 135.93, 135.33, 131.94, 130.54,
129.91, 128.88, 126.94, 126.55, 122.21, 119.74, 118.21, 115.28, 114.91, 110.71, 66.47.
HRMS (ESI+): m/z [M+H]+ calculated for C21H15ClN4O: 375.1016; found: 375.1019.
ACKNOWLEDGEMENTS
The authors acknowledge the financial assistance from the University of Delhi, (India)
under its strengthening R & D Doctoral Research Programme. PK is thankful to the UGC
(University Grants Commission, India), for providing a Junior Research Fellowship. AM
is thankful to Erasmus Mundus Action 2 “Namaste” project for providing Namaste
Fellowship. BKS and JVdE acknowledge DST (INT/BEL/P-4/2013), Govt. of India, New
Delhi for the financial assistance.
8

SUPPORTING INFORMATION
Full experimental detail, 1H and 13C NMR spectra have been provided in supporting
information. This material can be found via the “Supplementary Content” section of this
article’s webpage.
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Table 1. Optimization of reaction conditions.a
Entry Solvent
Time (min) Yield (%)b
1
2
3
4
5
6
7
8
9
DMF
DMF
DMF
PhMe
10
83
75
65c
65d
73
67
53
15
4 hour
30
1,4-Dioxane 10
CH3CN
EtOH
H2O
10
20
30
30
e
-
e
Neat
-
aReaction conditions: a mixture of 2-amino-N-(1H-benzo[d]imidazol-2-yl)benzamide
(1a) (1.0 mmol), 2-chlorobenzaldehyde (2a) (1.2 mmol) in DMF (2 mL) was irradiated at
80W maximum power, at a ceiling temperature of 130 °C; bisolated yield; creaction was
performed under conventional heating at 130 oC; dreaction was incomplete even after 30
min of irradiation under microwave condition; ereaction could not proceed and only
starting materials were isolated.
14

Table 2. Optimization of substrate scope of aldehydes.a
S. No. Compound R2
Yield (%)b
1
2-Cl-phenyl
83
3a
3b
3c
3d
3e
3f
2
2-Br-pheny
74
3
2-NO2-phenyl
phenyl
57
4
89c
93d
98d
71c
63c
84
5
4-CH3-phenyl
4-CH3O-phenyl
4-Cl-phenyl
6
7
3g
3h
3i
8
4-Br-phenyl
9
4-NO2-phenyl
4-Br-2-F-phenyl
2,6-dichlorophenyl
3,4-dichlorophenyl
2,6-difluorophenyl
ethyl
10
11
12
13
14
15
16
17
18
88
3j
89
3k
3l
69
85
3m
3n
3o
3p
3q
3r
74
cyclohexyl
72
furan
66
7-methoxycoumarin-4-yl
64c
7,8-dimethoxycoumarin-4-yl 71c
15

aReaction conditions : a mixture of 2-amino-N-(1H-benzo[d]imidazol-2-yl)benzamides
(1a) (1.0 mmol), aldehydes (2) (1.2 mmol) in DMF (2 mL) was irradiated at 80W
maximum power, at a ceiling temperature of 130 °C; bisolated yield; creaction was carried
out for 15 minutes; dreaction was carried out for 20 minutes.
16

Table 3. Important crystal data of compounds 3a.
Parameters
3a
CCDC deposition number
Empirical Formula
Formula weight
Temperature (K)
Crystal System
1440320
C21H15ClN4O
374.82
298.15
monoclinic
P21/n
Space Group
Unit Cell Dimension
a/Å = 11.5108(8)
b/Å = 9.1933(6)
c/Å = 16.3785(11)
α/° = 90
β/° = 97.978(6)
γ/° = 90
Volume Å3
1716.4(2)
4
Z
Density Calculated g/cm3
Absorption coefficient( ) mm-1
F(000)
1.450
0.242
776.0
Crystal size/mm3
Radiation
0.11 × 0.06 × 0.03
MoKα (λ = 0.71073)
17

6.02 to 52.038
2 range for data collection/°
Index ranges
-11 ≤ h ≤ 14
-6 ≤ k ≤ 11
-20 ≤ l ≤ 14
Reflection Collected
7247
Independent Reflections
Data/Restraints/parameters
Goodness of fit on F2
3373 [Rint = 0.0394, Rsigma = 0.0682]
3373/0/304
1.074
Final R indices [I>=2sigma(I)]
R indices (all data)
R1 = 0.0539, wR2 = 0.1006
R1 = 0.0899, wR2 = 0.1250
Largest difference peak and hole [e Ǻ-3] 0.19/-0.26
18

Table 4. Optimization of substrate scope of 2-aminobenzamides.a
S. No. Compound R
R1 Yield (%)b
4-F 62
1
2
3
4
5
6
7
Benzimidazol-2-yl
Benzimidazol-2-yl
5a
5b
5c
5d
5e
5f
5-I 64
6-methylbenzimidazol-2-yl -
87
83
87
67
89
6-cholrobenzimidazol-2-yl
-
-
-
-
Phenyl amino
phenyl
H
5g
aReaction conditions : a mixture of 4 (1.0 mmol), benzaldehyde (2d) (1.2 mmol) in DMF
(2 mL) was irradiated at 80W maximum power, at a ceiling temperature of 130 °C;
bisolated yield.
19

Scheme 1. Synthesis of 2,3-dihydroquinazolin-4(1H)-ones from 2-aminobenzamides.
20

Scheme 2. Competitive experiments a) between benzaldehydes and b) between 2-
aminobenzamides.
21

Figure 1. Some representative biologically important 2,3-dihydroquinazolinone
scaffolds.
22

Figure 2. ORTEP diagram of compound 3a with atomic numbering scheme at 30%
probability level.
23