Green protocol for the synthesis of 2-aryl-2,3-dihydroquinazoline-4(1H)-ones using Indion ina 225H resin

Article abstract of DOI:10.14233/ajchem.2015.18362

Synthesis of 2-aryl-2,3-dihydroquinazoline-4(1H)-ones is described by using new and novel heterogeneous catalyst, Indion Ina 225H resin. Anthranilamide was reacted with a series of aromatic aldehydes in presence of resin to afford various 2-aryl substituted 2,3-dihydroquinazoline-4(1H)-ones. The resin employed in these reactions can be recovered and reused.

Full text of DOI:10.14233/ajchem.2015.18362

Asian Journal of Chemistry; Vol. 27, No. 6 (2015), 2222-2224
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2015.18362
Green Protocol for the Synthesis of
2-Aryl-2,3-dihydroquinazoline-4(1H)-ones Using Indion Ina 225H Resin
*
K. SATISH REDDY, T. PARTHASARATHY, K. SANTOSH KUMAR and APURI SATYENDER
Department of Chemistry, University College of Science, Osmania University, Hyderabad-500 004, India
*Corresponding author: E-mail: apuri.satyender@yahoo.in
Received: 21 June 2014;
Accepted: 16 September 2014;
Published online: 17 March 2015;
AJC-16997
Synthesis of 2-aryl-2,3-dihydroquinazoline-4(1H)-ones is described by using new and novel heterogeneous catalyst, Indion Ina 225H
resin. Anthranilamide was reacted with a series of aromatic aldehydes in presence of resin to afford various 2-aryl substituted 2,3-
dihydroquinazoline-4(1H)-ones. The resin employed in these reactions can be recovered and reused.
Keywords: Green chemistry, Indion Ina 225H resin, 2,3-dihydroquinazolin-4(1H)-ones, heterogeneous catalyst.
involves condensation of anthranilamide and carbonyl com-
pounds. To accomplish this transformation, an assortment of
catalysts such as ionic liquids11, cellulose-SO3H12, NH4Cl13,
Amberlyst14, TiCl4/Zn15, CuCl216, trifluoroacetic acid17, and chiral
phosphoric acids18, etc. are employed. However, pitfalls asso-
ciated with these methods demands for development of a green
protocol involving low cost, easily available, easy to handle
and efficient catalysts.
INTRODUCTION
The ideology of green chemistry calls for the development
of new chemical reactivity's and reaction conditions that can
provide benefits for the chemical synthesis1. Employment of
heterogeneous catalysts in organic synthesis is one of these
greener methods and amongst various heterogeneous catalysts,
the use of resin as a catalyst has received paramount attention
over its companion reagents owing to its stability in water and
air2-4. In addition, the growing concern for the influence of the
chemical reagents on the environment as well as on human
body, recovery and reusability of the chemical reagents have
attracted the attention of synthetic organic chemists. Notably,
pharmaceutical industry has given more priority toward recovery
and reuse of chemical reagents to reduce the cost of a product
as well as the environmental burden.
Indion Ina 225H resin is a macro reticular, srongly acidic,
unifunctional, premium grade inexpensive cation exchange
resin containing sulfonic acid groups. It is an insoluble copolymer
with styrene divinylbenzene cross-linked matrix and appears
as golden yellow beads. The resin is extremely robust having
excellent physical and chemical characteristics5. Utility of this
resin as a catalyst for organic reactions6 has been scarcely
investigated and its unique nature prompted us to synthesize
heterocyclic scaffolds using this resin.
EXPERIMENTAL
Thin-layer chromatography (TLC) was performed on
Merck AL silica gel 60 F254 plates and visualized under UV
light. The column chromatography was performed using
1
Merck silica gel (60-120 mesh). The H NMR spectra were
recorded in DMSO-d6 at 400 MHz on aVARIAN spectrometer.
All the chemical shift values are reported in δ units using TMS
as internal standard. The Mass spectra were recorded using
PE-SCIEX-API-3000 system.
General procedure for synthesis of 2,3-dihydroquina-
zolin-4(1H)-ones (4a-o): Ina 225H resin (30 % w/w with respect
to 2) was added to a solution of anthranilamide (2) (1 mmol)
and aldehyde (3a-o, 1 mmol) in methanol (5 mL). The mixture
was stirred at room temperature for an appropriate time
(Table-1).After complete conversion (confirmed by TLC), the
catalyst was filtered and washed with methanol. Filtrate was
concentrated and purified by silica-gel column chromato-
graphy to afford compounds 4a-o.
2,3-Dihydroquinazoline-4(1H)-one moiety is an impor-
tant pharmacophore and privileged structure in medicinal
chemistry7-10. Its potential biological activity and wide natural
occurrence has fascinated many researchers to develop a plethora
of elegant synthetic methods. Of these, a simple and direct
approach for synthesis of 2,3-dihydroquinazoline-4(1H)-ones
2-(Naphthalen-2-yl)-2,3-dihydroquinazolin-4(1H)-one
(4a): 1H NMR (400 MHz, DMSO-d6) δ: 8.52 (d, J = 16 Hz,
1H) 8.32 (s, 1H), 8.05-7.90 (m, 2H), 7.77-7.62 (m, 2H), 7.50-

Vol. 27, No. 6 (2015)
Synthesis of 2-Aryl-2,3-dihydroquinazoline-4(1H)-ones Using Indion Ina 225H Resin 2223
O
O
7.48 (m, 3H), 7.30-7.22 (m, 1H), 7.14 (s, 1H), 6.77-7.65 (m,
2H), 6.42 (s, 1H). MS (ESI): m/z = 275 (M + H)+.
Indion Ina 225 H
Solven t, RT
CHO
NH
NH
2
+
Methyl 4'-(4-oxo-1,2,3,4-tetrahydroquinazolin-2-
N
H
NH
2
1
yl)-[1,1'-biphenyl]-4-carboxylate (4c): H NMR (400
2
3a
4a
MHz, DMSO-d6) δ: 8.35 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H),
7.82 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8 Hz, 2H), 7.62-7.61 (m,
3H), 7.23 (t, J = 8 Hz, 1H), 6.75 (d, J = 8 Hz, 1H), 6.66 (t, J =
8 Hz, 1H), 5.81 (s, 1H), 3.88 (s, 3H). MS (ESI): m/z = 359 (M
+ H)+.
2-(5-Methylthiophen-2-yl)-2,3-dihydroquinazolin-
4(1H)-one (4h): 1H NMR (400 MHz, DMSO-d6) δ: 8.41 (s,
1H), 8.66 (d, J = 4 Hz,1H), 7.32-7.31 (m, J = 8 Hz, 1H), 7.18
(s, 1H), 6.95 (s, 1H), 6.82-6.72 (m, 2H), 6.50 (s, 1H), 5.90 (s,
1H), 2.25 (s, 3H). MS (ESI): m/z = 243 (M-H)+.
Entry
Solvent
Acetonitrile
Toluene
Methanol
Ethanol
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
4.0
4.0
2.0
2.5
3.0
8.0
5.0
5.0
8.0
45
40
98
90
Isopropanol
Water
Dicholoromethane
Tetrahydrofuran
Ethyl acetate
86
NRc
20
22
15
aAll the reactions were carried out using 2 (1 mmol), 3a (1 mmol) and
Indion Ina 225; H resin (30 %, w/w) at room temperture. bIsolated
yields, cNR = no reaction
N-(4-(4-Oxo-1,2,3,4-tetrahydroquinazolin-2-yl)phenyl)-
1
acetamide (4i): H NMR (400 MHz, DMSO-d6) δ: 8.14
(s, 1H), 7.75 (s, 1H), 7.61 (d, J = 6.4 Hz, 1H), 7.59 (d, J =
2Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H), 7.25 (t, J = 6.8 Hz, 1H),
7.02 (s, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.68 (t, J = 7.2 Hz, 1H),
5.69 (s, 1H), 2.03 (s, 3H). MS (ESI): m/z = 280 (M-H)+.
2-(4-Bromo-2-fluorophenyl)-2,3-dihydroquinazolin-
Scheme-I: Synthesis of 2,3-dihydroquinazolin-4(1H)-ones
TABLE-1
INDION INA 225H CATALYZED SYNTHESIS OF
2,3-DIHYDROQUINAZOLIN-4-(1H)-ONESa
1
Time
(h)
3
3
4
4
4
2
5
S.
No.
Yield
(%)b
4(1H)-one (4n): H NMR (400 MHz, DMSO-d6) δ: 8.26 (s,
3
4
1H), 7.64-7.62 (m, 2H), 7.47-7.44 (m, 2H), 7.25 (t, J = 7.2
Hz, 1H), 6.74 (s, 1H), 6.78-6.89 (m, 2H), 6.02 (s, 1H). MS
(ESI): m/z = 321 (M + H)+.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Biphenyl-4-carbaldehyde
4-COOMe-biphenyl-4'-carbaldehyde
4-OMe-benzaldehyde
2,5-Di-OMe-benzaldehyde
2,3-Ethylenedioxy-5-carbaldehyde
Benzaldehyde
5-Me-thiophene-2-carbaldehyde
4-(N-Acetamido)benzaldehyde
4-Bromo benzaldehyde
b
c
d
e
f
g
h
i
95
93
96
97
95
98
92
90
95
95
96
95
97
88
2-(2,3-Dihydroxyphenyl)-2,3-dihydroquinazolin-
4(1H)-one (4o): 1H NMR (400 MHz, DMSO-d6): 9.48 (s, 1H),
8.71 (s, 1H), 7.85 (s, 1H), 7.61 (d, J = 8 Hz, 1H), 7.20 (t, J =
8.4 Hz,1H), 6.82-6.59 (m, 6H), 6.03 (s, 1H). MS (ESI): m/z =
255 (M-H)+.
3
2
j
4-Fluoro benzaldehyde
k
l
m
n
o
2
2
2
2
RESULTS AND DISCUSSION
2,6-Di-Cl-benzaldehyde
2-F-3-OMe-benzaldehyde
4-Br-2-F-benzaldehyde
Due to our interest toward the development of greener
chemical approaches for the synthesis of novel reaction inter-
mediates and heterocyclic compounds, we report herein the
synthesis of 2,3-dihydroquinazolin-4(1H)-ones by the reaction
of aromatic aldehydes and anthranilamide, using eco-benign
heterogeneous catalyst, Indion Ina 225 H (Scheme-I).
2,3-Di-OH-benzaldehyde
5
aAll the reactions were carried out using 2 (1 mmol), 3b-o (1 mmol)
and Indion Ina 225 H resin (30 %, w/w) at room temperature. bIsolated
yields
At the onset of our research, in order to establish optimal
reaction conditions, we choose 2-naphthaldehyde (3a) as model
aldehyde and screened various reaction conditions. Thus, the
reaction of 2-amino benzamide 2 (1 mmol), compound 3a
(1 mmol) in presence of Indion Ina 225 H resin (30 %, w/w)
in different solvents at room temperature was investigated and
the results are summarized (Scheme-I). The reaction was
initially carried out in acetonitrile at room temperature for 4 h
when the expected product 4a was obtained in 45 % yield
(entry 1). The use of other solvents such as toluene, dichloro-
methane, tetrahydrofuran and ethyl acetate were examined but
did not improve the product yield (entries 2, 7,8 and 9).Almost
quantitative yield was achieved within 2 h when reaction was
carried out in methanol (entry 4). Ethanol and isopropanol
(entries 4 and 5) were found to be less effective than methanol
under otherwise similar conditions for obtaining 4a. From these
findings, it was evident that alcoholic solvents are most suitable
for the synthesis of 4a in presence of Indion Ina 225 H resin.
Surprisingly, no product formation is observed when water is
employed as solvent even after 8 h (entry 6).
After establishing the best reaction conditions for synthesis
of 2,3-dihydroquinazolin-4(1H)-ones, the generality and scope
of this protocol has been further explored by reacting 2-amino
benzamide with a series of substituted aldehydes 3b-o using
Indion Ina 225 H resin in methanol at room temperature and
results are summarized in Table-1. The substitution group on
the aromatic ring had no apparent effect on the reaction yield.
Biphenyl aldehydes (entries 1 and 2), aldehydes with ether
functionality (entries 3-5) as well heteroaromatic aldehyde
(entry 7) afforded desired products in good yields. Dihydroxy
aldehyde (entry 14) also participated well in this reaction.
Similarly, aldehydes with halogen moiety at different positions
(entries 9-13) reacted smoothly to produce 2,3-dihydroquina-
zolin-4(1H)-ones in good yields. All the products 4b-o were
confirmed and characterized from 1H and NMR and mass spectral
data.
It is noteworthy to highlight that the catalyst could be
recycled five times without significant loss of activity. For
example, the treatment of anthranilamide 2 (1 mmol) with
4-bromobenzaldehyde 3j (1 mmol) in the presence of Ina 225H

2224 Reddy et al.
Asian J. Chem.
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This clearly demonstrates excellent recycling capability of
resin which in turn make it eco-friendly and economic.
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Conclusion
In conclusion, we have deveoped a new catalytic method
for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones using
anthranilamide, aldehydes and Indion Ina 225H resin.Attractive
features of this protocol are high yields, short reaction times,
simple procedure and recyclability and reusability of the catalyst.
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