A choline hydroxide catalyzed synthesis of 2,3-dihydroquinazolin-4(1: H)-ones in an aqueous medium

Article abstract of DOI:10.1039/c6ra15574j

A simple, metal and ligand-free protocol for the synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives using choline hydroxide (ChOH) as an effective catalyst in an aqueous medium has been developed. The good to high yield of the desired product is obtained, with a low environmental factor and high atom economy. ChOH was found to be recyclable up to six consecutive runs without significant loss in its activity. The use of water as an environmentally benign solvent, ease of work up and efficient recyclability of the catalyst makes this process more advantageous and greener.

Full text of DOI:10.1039/c6ra15574j

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A Choline hydroxide catalyzed synthesis of 2,3-dihydroquinazolin-
4(1H)-ones in an aqueous medium
Pravin N. Borase‡, Pranila B. Thale‡ and G. S. Shankarling*
Received 00th January 20xx,
Accepted 00th January 20xx
A simple, metal and ligand-free protocol for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones
derivatives using choline hydroxide (ChOH) as an effective catalyst in an aqueous medium has been
developed. The good to high yield of the desired product is obtained, with low environmental factor
and high atom economy. The ChOH was found to be recyclable up to six consecutive runs without
significant loss in its activity. The use of water as an environmentally benign solvent, ease of work up
and efficient recyclability of the catalyst makes this process more advantageous and greener.
DOI: 10.1039/x0xx00000x
www.rsc.org/
dihydroquinazolin-4(1H)-ones. But, this method also suffers
few drawbacks like the use of binary solvent mixture and
1. Introduction
comparatively longer reaction time is needed. Owing to the
above limitations, the development of an inexpensive and
environmentally benign catalyst for 2,3-dihydroquinazolin-
4(1H)-ones synthesis has been a major area of the research.
2,3-dihydraquinazolinones, a nitrogen containing heterocyclic
compounds are found as the core structural skeleton in a
variety of drug molecules1–4 (Scheme 1).
2,3-
dihydraquinazolinones derivatives have drawn much attention
due to their potential in biological and pharmaceutical
activities such as antidepressant, analgesic, diuretic, sedative,
antihistamine and antihy-pertensive agent5,6. It is also useful in
various anticancer activities like inhibition of tubulin
formation, inhibition against VEGFR2 tyrosine kinase and cell
proliferation7. Generally, ortho-amino or ortho-nitro benzoic
acid derivatives are used for 2,3-dihydroquinazolin-4(1H)-ones
synthesis. Grieß et al, has reported the first synthesis of
quinazolinone scaffold from anthranilic acid and cyanogen8.
Later, Von Niementowski optimized the reaction involving the
fusion of anthranilic acid analogues with amides9. In recent
years, synthesis of 2,3-dihydroquinazolin-4(1H)-ones has been
Cl
O
O
O
H2N
S
NH
N
O
Cl
Cl
N
H
N
Quinethazone
Cloroqualone
O
O
N
N
O
H2N
S
N
O
Cl
N
H
Methylmethaqualone
Metolazone
reported in the presence of various acid and metal catalyst10–
Scheme 1: Selected examples of pharmaceutically active
quinazolinone derivative
13
.
More
recently,
synthesis
of
2-substituted
dihydroquinazolinones was published by Jian Wu and co-
worker using anthranilamide and carbonyl compounds in the
presence of β-cyclodextrin as a catalyst14. Other homogeneous
In the current era, aqueous media for organic synthesis has a
great importance in the context of greener solvent media18–20
.
15
16
Water is
a readily available, non-toxic, environmentally
catalysts such as K3PO4 and ZnCl2 have also been reported
for effective cyclization of the dihydroquinazolinones.
However, their major shortcomings are need of higher
temperature, longer reaction time and difficulty in the
recycling of the catalyst. To overcome the issue of separation,
recently Tamaddon et al17 have reported Amberlyst A26-OH as
friendly and has a strong hydrogen bonding ability, which can
lead to unusual reactivity which is not seen in traditional
organic solvents. Water is potentially safer than other organic
solvents and considered as an environmentally benign and
non-hazardous solvent21–25
Choline chloride is cheaply available and choline based ionic
.
a
heterogeneous catalyst for the synthesis of 2,3-
liquids plays
a crucial role in a variety of organic
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transformations26–29
.
It also offers attractive industrial solvent at 80oC. Similarly, we have studied the role of various
forecasts in terms of sustainable and viable chemistry30. It has bases over the different substrates of aldehyde (benzaldehyde,
several advantages in terms of availability, low price, p-chloro benzaldehyde and p-tolualdehyde). For this, we have
biodegradability and environmentally benign features31–33
.
conducted a series of reaction with different inorganic bases
Choline hydroxide possesses a strong basic characteristic. and ChOH. From the table 2, it can be seen that the yield of
Therefore, the developed protocol offers use of the the desired product is maximum when choline hydroxide is
environmentally benign solvent and the recyclable catalyst for used as a catalyst. Increasing the amount of inorganic bases
the synthesis of 2,3-dihydroquinazolin-4(1H)-ones.
will not improve the yield of the product15. With the optimised
a
Herein, we report an efficient, metal and ligand free, parameters in hand we have also performed wide substrate
economically inexpensive catalytic strategy for the synthesis of study with different aliphatic, aromatic and heteroaromatic
2,3-dihydroquinazolin-4(1H)-ones derivatives in an aqueous aldehydes for the synthesis of 2,3-dihydroquinazolin-4(1H)-
medium (Scheme 2). The recyclable and inexpensive catalyst ones derivatives (Table 3). Good to excellent yields of the
in an aqueous medium stand out, to be a valuable alternative desired product were obtained with heterocyclic, aliphatic and
for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones electron withdrawing aromatic aldehydes. However, electron
derivatives.
donating aromatic substituents provided moderate yield of the
desired product.
Table 1: Optimization of reaction conditions
Yield
(%)
Entry
Catalyst
V/V %
Temp
Time
Solvent
Effect of Catalyst
1
2
3
4
5
6
Neat
ChCl
ChOH
ChOH
ChOH
ChOH
--
80°C
80°C
80°C
80°C
80°C
80°C
24h
24h
6h
2h
30min
30min
Water
Water
Water
Water
Water
Water
NR
NR
86%
89%
96%
96%
30%
10%
20%
30%
40%
Scheme 2: General reaction scheme
2. Result and Discussion:
Effect of other basic catalyst
In the current protocol, we have used 2-aminobenzonitrile and
benzaldehyde as a model substrates for the optimisation of
the reaction condition (Scheme 2). We have thoroughly
investigated the effect of base by conducting series of reaction
with different inorganic bases, such as KOH, NaOH, Na2CO3,
K2CO3, and Cs2CO3 which gave the desired product in the range
60% to 40% yields (Table 1). Whereas, in the presence of ChOH
as a catalyst in an aqueous medium we obtained the desired
product in good yield 96% (Table 1, Entry 5). The higher yield
of the product was obtained with ChOH because it acts as a
homogeneous catalyst in an aqueous medium which helps to
improve the solubility of the reactants through hydrogen
bonding and hence increases the rate of the reaction. Next, we
have screened various solvents among which water was the
most effective solvent for cyclization of the Schiff base
intermediate. (Table 1, Entry 21). The poor yield of the target
product was obtained in toluene and dioxane solvents.
However, other solvents such as methanol, ethanol and
dimethylformamide (DMF) gave low yield in comparison to
that of water. To determine the catalyst loading, a model
reaction of 2-aminobenzonitrile and benzaldehyde with the
different percentage of ChOH in water was carried out. The
reaction occurred smoothly in the presence of 30% ChOH as a
catalyst and water as a solvent, affording a single product in
96% yield. Increasing the amount of catalyst, more than 30%
showed no substantial improvement in the yield (Table 1,
Entry 6). The suitable temperature for the reaction was found
to be 80oC. (Table 1, Entry 14). Therefore, optimised reaction
parameter includes 1.0 mmol of 2-aminobenzonitrile, 1.2
mmol of aldehyde, 30% of ChOH as a catalyst and water as a
7
8
9
10
11
K2CO3
Cs2CO3
Na2CO3
NaOH
KOH
2.5a
2.5a
2.5a
2.5a
2.5a
80°C
80°C
80°C
80°C
80°C
8h
8h
8h
8h
8h
Water
Water
Water
Water
Water
40%
35%
30%
50%
60%
Effect of Temperature
12
13
14
15
ChOH
ChOH
ChOH
ChOH
30%
30%
30%
30%
40°C
60°C
80°C
30min
30min
30min
Water
Water
Water
Water
45%
70%
96%
96%
100°C 30min
Effect of Solvent
16
17
18
19
20
21
ChOH
ChOH
ChOH
ChOH
ChOH
ChOH
30%
30%
30%
30%
30%
30%
80°C
80°C
80°C
80°C
80°C
80°C
4h
4h
6h
8h
8h
MeOH
EtOH
DMF
Toluene
Dioxane
Water
80%
85%
60%
45%
50%
96%
30min
Conditions: 2-aminobenzonitrile (1mmol), Benzaldehyde
(1.2mmol), 30% V/V of ChOH in water 3.5mL, Base used (2.5
equiv.)
a
Scheme 3: Substrate study with base catalyst
2 | J. Name., 2012, 00, 1-3
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amount of waste generated with respect to the total amount
of product formed and it was found in the range of 14 to 30%
(Table 3). This is in a good accordance with the principle of
green chemistry. Thus, ChOH based catalytic protocol
provides an astonishing reactivity in presence of water for the
synthesis of 2,3-dihydroquinazolin-4(1H)-ones.
Table 2: Effect of base catalyst over aldehyde substrate.
Yield (%)c, Time
Catalyst
Entry Catalyst
loading
30%a
R2= -H
R2= -CH3
R2= -Cl
96
(30min)
89
(110min)
Traces
(8h)
Traces
(8h)
90
(50min)
Traces
(8h)
Traces
(8h)
1
2
3
4
ChOH
K2CO3
Table
dihydroquinazolinone-4(1H)-ones
< Insert Table 3 >
3:
ChOH
catalyzed
synthesis
of
2,3-
2.5b
2.5b
2.5b
40 (8h)
35 (8h)
30 (8h)
Cs2CO3
Na2CO3
Conditions: 2-Aminobenzonitrile (1mmol), aldehyde (1.2mmol),
30% V/V of ChOH in water 3.5mL, Temp: 80°C; aIsolated yield; bE-
factor = environmental factor
Traces
(8h)
Traces
(8h)
5
6
NaOH
KOH
2.5b
2.5b
50 (8h)
60 (8h)
20 (8h)
45 (8h)
25 (8h)
50 (8h)
3. Experimental section:
Conditions:
(1.2mmol), 30% V/V of ChOH in water 3.5mL, Base used (2.5
2-Aminobenzonitrile
(1mmol),
aldehyde
a
b
3.1 Materials and Methods:
equiv.) and Temp: 80°C; CIsolated yield
IR spectra of the compounds were recorded on Jasco FT-IR
ATR-PRO/4100 spectrophotometer. 1H NMR spectra were
recorded on Agilent 500 MHz spectrometer in DMSO solvent.
Mass spectral data were obtained with a Finnigan LCQ
Advantage max spectrometer. Choline chloride, Pottasium
hydroxide, Methanol, Benzaldyhde and its derivatives were
purchased from S.D. Fine Chemical Ltd., India. and 2-
Based on the present experimental observations and literature
reports34–38, the proposed reaction mechanism is depicted in
scheme 4. The reaction was initiated with the formation of
Schiff base intermediate between aldehyde and 2-
aminobenzonitrile in the presence of ChOH catalyst. Then
simultaneously, nucleophilic attack of counter hydroxide ion of
ChOH on the electrophilic carbon of nitrile was favoured
because of which intramolecular cyclization was initiated. The
nucleophilic attack of nitrile nitrogen on the electron-deficient
carbon of Schiff base resulted in the formation of cyclized
product through 1,5 proton shift to give 2,3-dihydroquinazolin-
4(1H)-ones derivative. To confirm the above proposed reaction
mechanism, we have isolated the Schiff base intermediate
(Schiff base INT_1) and characterised it by using 1H-NMR
(Figure S2) and ESI-MS mass analysis technique.
aminibenzonitrile
Chemicals.
was purchased from Sigma Aldrich
3.2 General procedure for the synthesis of choline hydroxide
(ChOH):
To a solution of choline chloride (1 mol) in methanol, one mole
equivalent of potassium hydroxide was added slowly at room
temperature. Later, it was heated at 60oC for 12 h with
constant stirring. After cooling to room temperature, the
reaction mixture was filtered to remove solid KCl salt. The
obtained solution was concentrated to remove excess of
methanol and was used without further purification.
3.3 Determination of Basicity of ChOH:
The basicity of the ChOH hydroxide was determined by the
conventional acid-base titration method. 1.5 ml of ChOH was
taken in 50 ml of water and titrated against the standardized
0.1M HCl solution using phenolphthalein as an indicator. The
concentration of OH- ions was found to be 0.0052 meq/mL.
3.4 General procedure for the synthesis of 2,3-dihydroquinazolin-
4(1H)-one derivatives:
In a general procedure, a mixture of 2-aminobenzonitrile (1.0
mmol), benzaldehyde (1.2 mmol), ChOH 30% volume by
volume in water (3.5 ml) was stirred at 80°C and the progress
of the reaction was monitored on the TLC. After completion of
the reaction the reaction mass was cooled, the solid product
was filtered and washed with water. The crude product was
purified by column chromatography on silica gel using hexane:
ethyl acetate (6:4) as an eluent to obtain the desired product.
Yield 96%, 0.67 g, m.p. 208°C. All compounds were analysed by
melting point, mass, IR and 1H-NMR techniques.
Scheme 4: Plausible reaction mechanism
The intrinsic atom economy was found to be 100%, which
markedly influence the greenness of the current protocol. The
environmental factor (E-factor) was calculated to understand
the amount of waste generated and effectiveness of the
protocol. The E-factor was calculated form the ratio of total
3.5 Recyclability studies:
To understand the process viability and feasibility, the reaction
of 2-aminobenzonitrile and benzaldehyde was scaled-up to 1 g.
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The ChOH was recovered and used for recyclability study
(Figure 1). After filtration of the crude product from reaction 3.
mass, the filtrate was used for the next recycle study. The
ChOH was recycled up to six consecutive runs without any 4.
significant loss in its activity. The Fresh and reused ChOH have
been characterized by ATR-FTIR spectroscopy. The 5.
comparative study of the fresh and reused catalyst illustrate
that, there is no change in the functional group values in the
FT-IR spectrum (Figure S1). The broad absorption peak at 3352 6.
cm-1 is characteristics of O-H stretching vibration. The band at 7.
1293 and 1078 cm-1 corresponds to stretching vibration of C-N 8.
and C-O bond respectively. The C-H bending vibrations was
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4. Conclusion:
In summary, we have demonstrated a simple, metal and ligand
free strategy for the synthesis of 2,3-dihydroquinazolin-4(1H)-
ones derivatives in an aqueous medium. The catalyst was
efficient and recyclable up to six consecutive runs. The low
range of E-factor, high atom economy, use of greener aqueous
media and recyclable catalyst satisfies the principles of green
chemistry.
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Authors are thankful to Technical Education Quality
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Notes
‡ These others contributes equally
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Figures and Table captions
1) Scheme 1: Selected examples of pharmaceutically active quinazolinone derivative
2) Scheme 2: General reaction scheme
3) Scheme 3: Substrate study with base catalyst
4) Scheme 4: Plausible reaction mechanism
5) Table1: Optimization of reaction conditions
6) Table 2: Effect of base catalyst over aldehyde substrate.
7) Table 3: ChOH catalyzed synthesis of 2,3-dihydroquinazolin-4(1H)-ones
8) Figure 1: Recyclability study of ChOH catalyst
Scheme 1: Selected examples of pharmaceutically active quinazolinone derivative.
Scheme 2: General reaction scheme.
Scheme 3: Substrate study with base catalyst

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Scheme 4: Plausible reaction mechanism

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Table1: Optimization of reaction conditions
Entry.
Catalyst
V/V % Temp
Time
Solvent Yield (%)
Effect of Catalyst
1
2
3
4
5
6
Neat
ChCl
--
80°C
80°C
80°C
80°C
80°C
80°C
24h
24h
Water
Water
Water
Water
Water
Water
NR
NR
30%
10%
20%
30%
40%
ChOH
ChOH
ChOH
ChOH
6h
86%
89%
96%
96%
2h
30min
30min
Effect of other basic catalyst
6
7
K2CO3
Cs2CO3
Na2CO3
NaOH
KOH
2.5a
2.5a
2.5a
2.5a
2.5a
80°C
80°C
80°C
80°C
80°C
8h
8h
8h
8h
8h
Water
Water
Water
Water
Water
40%
35%
30%
50%
60%
8
9
10
Effect of Temperature
11
12
13
14
ChOH
ChOH
ChOH
ChOH
30%
30%
30%
30%
40°C
60°C
30min
30min
30min
30min
Water
Water
Water
Water
45%
70%
96%
96%
80°C
100°C
Effect of Solvent
15
16
17
18
19
20
ChOH
ChOH
ChOH
ChOH
ChOH
ChOH
30%
30%
30%
30%
30%
30%
80°C
80°C
80°C
80°C
80°C
80°C
4h
MeOH
EtOH
80%
85%
60%
45%
50%
96%
4h
6h
DMF
8h
Toluene
Dioxane
Water
8h
30min
Conditions: 2-aminobenzonitrile (1mmol), Benzaldehyde (1.2mmol), 30% V/V of ChOH in water
3.5mL, aBase used (2.5 equiv.)

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Table 2: Effect of base catalyst over aldehyde substrate.
Yield (%)c, Time
R2= -CH3
96 (30min) 89 (110min) 90 (50min)
Catalyst
loading
Entry
Catalyst
R2= -H
R2= -Cl
1
2
3
4
5
6
ChOH
K2CO3
Cs2CO3
Na2CO3
NaOH
KOH
30%a
2.5b
2.5b
2.5b
2.5b
2.5b
40 (8h)
35 (8h)
30 (8h)
50 (8h)
60 (8h)
Traces (8h) Traces (8h)
Traces (8h) Traces (8h)
Traces (8h) Traces (8h)
20 (8h)
45 (8h)
25 (8h)
50 (8h)
a
Conditions: 2-Aminobenzonitrile (1mmol), aldehyde (1.2mmol), 30% V/V of ChOH in
water 3.5mL, bBase used (2.5 equiv.) and Temp: 80°C; CIsolated yield
Table 3: ChOH catalyzed synthesis of 2,3-dihydroquinazolin-4(1H)-ones
Starting
material
Time
(min)
Yield
(%)a
E-
Entry
1
Product
factorb
30
50
96%
90%
86%
85%
92%
0.09
0.17
0.22
0.24
0.15
2
3
4
5
80
90
100
6
7
110
120
89%
85%
0.18
0.24

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8
9
90
90
90%
89%
0.17
0.18
O
NH
10
11
100
90
86%
90%
0.23
0.17
N
H
OCH3
12
13
14
15
90
90
84%
88%
82%
89%
0.24
0.17
0.28
0.18
120
90
16
17
100
120
86%
90%
0.22
0.16
18
120
86%
0.21
Conditions: 2-Aminobenzonitrile (1mmol), aldehyde (1.2mmol), 30% V/V of ChOH in water
3.5mL, Temp: 80°C; aIsolated yield; bE-factor = environmental factor

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Figure 1: Recyclability study of ChOH catalyst

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A Choline hydroxide catalyzed synthesis of 2,3-dihydroquinazolin-4(1H)-ones in
an aqueous medium
Graphical abstract