Synthesis of 2,3-dihydroquinazolinones and quinazolin-4(3H)-ones catalyzed by graphene oxide nanosheets in an aqueous medium: "on-water" synthesis accompanied by carbocatalysis and selective C-C bond cleavage

Article abstract of DOI:10.1039/c6ra00388e

Graphene oxide (GO) nanosheet catalyzed new and straightforward strategies for the construction of 2,3-dihydroquinazolinones and quinazolin-4(3H)-ones starting from anthranilamide (2-aminobenzamide) and an aldehyde/ketone in aqueous medium at room temperature have been realized. This catalyst is also found to be efficient for the expedient construction of quinazolin-4(3H)-ones starting from anthranilamide and a β-ketoester/1,3-diketone following selective C-C bond cleavage of the β-ketoester/1,3-diketone at an elevated temperature under metal and oxidant free conditions.

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Synthesis of 2,3-dihydroquinazolinones and quinazolin-4(3H)-one
catalyzed by Graphene Oxide nanosheets in aqueous medium: “on-
water” synthesis accompanied by carbocatalysis and selective C-C bond
cleavage
5
Nazia Kausara, Indranil Royb, Dipankar Chattopadhyayb, Asish R. Dasa*
a
Department of Chemistry, University of Calcutta, Kolkata-700009, India
bDepartment of Polymer Science and Technology, University of Calcutta, 92 A.P.C.
Road, Kolkata 700009, India.
10 *Corresponding author. Tel.: +913323501014, +919433120265; fax: +913323519754;
E-mail address: ardchem@caluniv.ac.in, ardas66@rediffmail.com (A R Das)
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Graphene oxide (GO) nanosheet catalyzed new and straightforward strategies for the construction of 2,3-
15 dihydroquinazolinones and quinazolin-4(3H)-one starting from anthralinamide (2-aminobenzamide) and
aldehyde/ketone in aqueous medium at room temperature have been materialized. This catalyst is also
found to be efficient towards the expedient construction of quinazolin-4(3H)-one starting from
anthranilamide and β-ketoester/1,3-diketone following selective C-C bond cleavage of β-ketoester/1,3-
diketone at some elevated temperature under metal and oxidant free conditions.
20
cyclocondensation reaction of anthranilamide and carbonyl
45 compounds involving a carbocatalyst, graphene oxide (GO)
nanosheets. After successful accomplishment to design both 2,3-
dihydroquinazolinones and quinazolin-4(3H)-one, we proceeded
to another synthetic route for the construction of the oxidized
product (quinazolin-4(3H)-one) starting from anthranilamide and
50 1,3-diketones/ β-ketoesters via selective C-C bond cleavage of
1,3-diketones/ β-ketoesters involving the same catalyst in
aqueous medium under oxidant free condition.
Introduction
N-Heterocyclic compounds are considered to be the most profuse
and integral scaffolds that are found in a large number of
bioactive natural products, synthetic drugs and pharmaceuticals.1
25 Among the diversified N-heterocyclic compounds, 2,3-
dihydroquinazolinones and quinazolin-4(3H)-one are vastly
significant class of heteroaromatic compounds that are ubiquitous
in the field of pharmaceuticals, therapeutically potent and
biologically active .2 Owing to the large number of applications of
30 these heterocyclic moiety, synthesis of these compounds is
largely an affair of interest. Some attempts for the synthesis of
these compounds have been reported in the literature in recent
decades and reported methods3 though claim good results in
many instances, still development of efficient, simple, metal free
35 approach using recyclable catalysts that offers a huge substrate
scope and covers up most of the features of green chemistry4 is
desirable and of course in demand.
Recalling the previously developed methods and their
shortcomings which have included the application of hazardous
40 organic solvents, strongly acidic conditions, expensive moisture-
sensitive catalysts, extended reaction times, high reaction
temperatures, and also tedious work-up conditions, we intended
55
Fig. 1 Quinazolin-4(3H)-one based natural products
Now-a-days selective C−C bond cleavage is an important and
essential topic in the field of organic synthesis5, which allows the
to devise
a new and simple catalytic method for the
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construction of a new C−C bond directly from inert starting
materials. It was well demonstrated by the work of Yashuro et al,
where camphorsulfonic acid was employed to furnish quinazolin-
4(3H)-one moiety from 1,3-dicarbonyl compounds in ethyl
lactate-water medium at 100 oC.6 Furthermore, selective C-C
bond cleavage was also realized during the formation of
quinazolin-4(3H)-one from β-ketoesters employing phosphorous
acid in ethanol medium7. Despite having some advances in this
field , the development of selective C−C bond cleavage by
10 catalytic mode is a challenging problem in organic chemistry
involving metal-free and oxidant free strategies .9 To conquer
these challenges, we devised a new strategy for the C-C bond
cleavage under metal and oxidant free conditions and
successfully developed another synthetic protocol for the
15 construction of quinazolin-4(3H)-one derivatives from
anthranilamide and 1,3-diketone/β-keto ester allowing selective
cleavage of C-C bond of 1,3-diketone/β -keto ester in presence of
GO nanosheets.
5
Fig. 2 FTIR and XRD pattern of GO nanosheets
55
HRTEM and FESEM images (Fig. 3) of GO nanosheets disclose
that graphene oxide is composed of a few layers, resulting in a
high surface area responsible for efficient catalytic activity.
60
Fig 3. FESEM and TEM images of GO nanosheets
In continuation of our ongoing research10 in developing new
20 catalytic system for the construction of various biologically
significant molecules with the aid of sustainable chemistry, GO
nanosheets being a carbocatalyst11 was found to be the most
efficient for our desired transformations. Recently, GO
nanosheets has attracted enormous interest to the development
25 of composite materials and catalysts12, due to their remarkable
physical, chemical, electrical characteristics and a very high
specific surface area to weight13.In the field of organic synthesis,
nanostructured polycarbon acids are considered to be more
vigorous in aqueous media which facilitates us to report GO
For the sake of validation of graphene oxide nanosheets to be the
65 key for inferring the reactions in aqueous media, we have carried
out screening tests employing a series of catalysts and solvents.
Model substrate for the initial screening was anthranilamide (1)
and m-nitrobenzaldehyde (2) as described in Table 1. Some of
previously discussed methods involves the cyclocondensation of
70 anthranilamide with aldehyde using p-sulfonic acid
calix[4]arene15,
functionalized,
nanoparticles17
Fe3O4
piperidine-4-carboxylic
(Fe3O4-SA-PPCA
nanoparticles16,
Sulfamic
acid-
acid
Fe3O4
ionic-
nanoparticles),
liquids18,2-(Nmorpholino)ethanesulfonic acid (MES) in aqueous
75 ethanol19 suffer from one or more disadvantages as previously
mentioned. Therefore, we have intended to design a simple,
efficient, new and green route for the cyclocondensation reaction
with a larger substrate scope. Our initial attempts involved
reaction with, polyethylene glocol-SO3H (PEG-SO3H) reduced
80 graphene oxide (RGO), polyethylene glycol-SO3H-bearing solid
acid catalyst (PEG-SAC), SnO2 quantum dots, and nano
CuFe2O4. In most of the cases time required for the generation of
the desired product was more as well as the isolated yield was not
sufficient. Hence, the search of appropriate catalyst was in
85 demand. When the reaction was carried out in presence of nano
GO, it was found that the desired product was obtained in higher
yield than before (Table 1, entry 8). Result encouraged us to
perform the reaction involving GO and it was found that these
GO nanosheets offered maximum yield of the product within
90 minimum period of time in aqueous medium. When 25 mg GO
nanosheets was applied, it was found to be the most effective in
promoting the formation of desired product with maximum yield
(Table 1, entry 11) and shorter reaction time. The recyclability of
GO nanosheets was also very high in aqueous media. After the
95 reaction, GO nanosheets could be recycled easily and castoff in
the next run. The recyclability chart of the catalytic potential of
GO nanosheets is shown in Fig. 5 (recovery amount 90% after
5th run). Elemental analysis of fresh GO nanosheets provided - C
62.01% and H 2.84% respectively and in recycled GO it was
100 found to be 61.98% and 2.86% respectively. The XRD image of
30 nanosheets,
a readily available, inexpensive and efficient
carbocatalyst11 that enhances the latitude of our current research.
Result and discussion:
Preparation of the carbocatalyst i.e. GO nanosheets was done by
the slight modification of known methods14. XRD study and
35 FTIR (Fig. 2) spectrum were recorded to identify the nature of
various chemical functionalities present on the graphene oxide
nanosheets and its dispersion in water. Various functional groups
on GO nanosheets were appeared on oxidation of graphite
powder. These functional groups are bonded on either edges and
40 or basal planes of graphitic layers. Furthermore, trapped water
molecules are suspected to be present between these layers and
responsible for expansion of the interlayer spacing in graphene
oxide nanosheets. An intense and broad peak appeared at 3424
cm-1 corresponds to the stretching mode of an O–H bond and
45 suggests the abundance of hydroxyl groups in graphene oxide.
The strong band at 1722 cm-1 represents carboxylic acid and
carbonyl groups. FTIR bands at 1224 cm-1 and 1053 cm-1 are
appeared due to the presence of C–OH and C–O of epoxy groups
respectively, in GO nanosheets.
50
2
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recovered GO nanosheets is also identical with the XRD image of
fresh GO (Fig. 4).
5
Fig. 4 XRD pattern of recovered GO nanosheets
Table 1 Optimization of Reaction Conditionsa
Entry
Catalyst
Catalyst Free
Solvent
Water
EtOH
Water
Water
Water
EtOH
EtOH
EtOH
Water
Water
Water
Temperature (oC)
Time (h)
10
Yieldb (%)
1
2
100
Reflux
80
trace
trace
65
-
Catalyst Free
10
3
PEG–SO3H (10 mg)
2
4
RGO (25 mg)
r.t
0.5
0.5
10
5
PEG-SAC (25 mg)
r.t
30
-
6
SnO2-QDs (10 mol%)
Reflux
Reflux
Reflux
80
7
Nano CuFe2O4 (10 mol%)
Graphene Oxide nanosheets (10 mg)
Graphene Oxide nanosheets (10 mg)
Graphene Oxide nanosheets (15 mg)
Graphene Oxide nanosheets (25 mg)
10
-
8
3
80
85
85
93
9
0.5
0.25
0.25
10
11
r.t
r.t
aReaction conditions: anthranilamide (1 mmol), meta- nitrobenzaldehyde (1 mmol)
10 b Isolated yields of pure products
In order to predict the active site present in GO, we have
transformation. Therefore, carboxylic acid functional group
designed the model reaction taking various small molecules like 20 present in GO is assumed to be the active reaction centre and
benzoic acid, ethylene glycol, meso-1,2-diphenylethane-1,2-diol,
15 sulphuric acid, styrene oxide, stilbene oxide and 2-iodophenol as
the catalyst (Table 2). Among the applied catalysts, benzoic acid
and sulphuric acid have proven their efficiency while benzoic
responsible for the desired transformations.
Utilizing the optimized reaction condition, synthesis of
compound 3a-k (involving electronically varied aromatic,
aliphatic and heteroaromatic aldehydes 2) was achieved with an
acid showed its extra potential towards the desired 25 excellent
yield
(Table3).
30
Fig.5 Reusability study of GO nanosheets
35
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Table 2 Reactions for Evolution of Active Site in Catalyst (GO)
Entry
Catalyst
Solvent
Temperature (oC)
Time (h)
0.25
Yieldb (%)
1
2
Benzoic acid (10 mol%)
Water
Water
r.t
r.t
65
-
Ethylene glycol (10
mol%)
0.25
3
1,2-diphenylethane-1,2-
diol (5mol%)
water
r.t
0.5
-
4
5
H2SO4 (13 mol%)
Water
Water
r.t
r.t
0.25
0.5
25
-
Styrene Oxide (10
mol%)
6
7
Stilbene Oxide
(10mol%)
water
r.t
r.t
0.5
0.5
-
-
2-iodophenol (10 mol%)
Water
Table 3 Synthesis of diversified 2,3-dihydroquinazolinone derivatives a
1
2
3
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3a, 20min, 94%
3d, 12min, 95%
3g, 20 min, 92%
3b, 25min, 92%
3e, 12 min, 95%
3c, 10min, 96%
3f, 12min, 95%
3i, 25min, 88%
3h, 12 min, 97%
3l, 15min,90%
3j, 20min, 89%
3k, 25min, 89%
3m, 25min, 88%
3o,15min, 92%
3n, 25min, 87%
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3r, 30min, 85%
3p, 15min, 90%
3q, 20min, 94%
3s, 25min, 89%
aReaction conditions: anthranilamide (1 mmol), aldehyde (1 mmol), GO nanosheets (25 mg), 3 ml H2O at r.t for stipulated time
To further explore the substrate scope, various ketones20 (4) were
then investigated as depicted in Table 4. A wide range of
activated as well as unactivated ketones, with electron-deficient
and electron-rich aryl groups, cyclic & acyclic ketones were
highly compatible under the developed protocol and provided
excellent yield of the corresponding products (5a-l) at room
temperature.
5
10 In all cases, the progress of the reaction was monitored by TLC.
1
The structures of the desired products were characterized by H ,
13C NMR and IR spectral data. The X-ray crystal structure of 2-
(4-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (3h) (Fig. 6), 2-
methyl-2-phenyl-2,3-dihydroquinazolin-4(1H)-one (5a) (Fig. 7)
15 and 1'H-spiro[cyclopentane-1,2'-quinazolin]-4'(3'H)-one (5j)
(Fig. 8) further confirmed the product identity.
Fig. 7 Single crystal structure of compound 5a (CCDC) 1416677
25
Fig. 8 Single crystal structure of compound 5j (CCDC) 1057349
20
Fig.6 Single crystal structure of compound 3h (CCDC) 1057348
30
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Table 4 Synthesis of diversified 2, 3-dihydroquinazolinones derivativesa
1
4
5
5b, 40min 85%
5c, 40min, 89%
5a, 35min, 86%
5e, 40min, 83%
5d, 45min, 84%
5f, 30min, 85%
5i, 20min, 95%
5g, 30min,89%
5j, 20min, 95%
5h, 30min, 87%
5k, 35min,83%
5l, 30min, 85%
aReaction conditions: anthranilamide (1 mmol), ketone (1 mmol), GO nanosheets (25 mg), 3 ml H2O at r.t for stipulated time
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Result obtained applying the developed protocol in the
cyclocondensation of anthranilamide and carbonyl compounds
encouraged us to further extend this methodology for the
synthesis of quinazolin-4(3H)-one derivatives and the oxidized
transformation (involving electronically varied nature of
aldehydes 2’) at room temperature. Interestingly, during this
reaction condition no side product was evolved through the
oxidation of the starting material rather the reaction has produced
5
products21 (6a-i) were realized when the reaction was carried out 15 only the targeted molecule. In this study also, the progress of the
in presence of oxone (Table 5). In this case, GO nanosheet solely
was unable to provide the oxidized product at room temperature.
10 Employing oxone with GO, led us to achieve the desired
reaction was monitored by TLC. The structures of all the
products were well characterized through the analysis of 1H , 13
NMR and IR spectral data.
C
20 Table 5 Synthesis of diversified quinazolin-4(3H)-one derivative
1
2’
6
6b, 2h, 92%
6a, 2h, 94%
6c, 0.5h, 96%
6f, 2h, 95%
6e, 2h, 95%
6h, 2h, 95%
6d, 1.5, 95%
6g, 2h, 95%
6i, 2h, 95%
aReaction conditions: anthranilamide (1 mmol), aldehyde (1 mmol), GO nanosheets (25 mg), Oxone (307 mg), 3 ml H2O at r.t for stipulated time
8
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We then tried to understand the insight of the reaction which is
represented in Scheme 1. The first step involves the condensation
of anthranilamide (1) with aldehyde/ketone (2/2’/4) promoted by
the catalyst (GO nanosheets) to produce imine intermediate (I).
cleavage applying
the same catalyst. Treatment of
anthranilamide with either acetyl acetone, benzoyl acetone or β-
keto ester (ethyl acetoacetate), offered the same compound, 2-
methylquinazolin-4(3H)-one with different yields (Table 6).
5
The imine part of the intermediate I could be activated by the 25 Obtained results on analysis, gave the idea about the selective
catalyst and intermediate I subsequently converted into 2,3-
dihydroquinazolinone (3/5) by intramolecular nucleophilic attack
by the nitrogen of amide functionality on the imine carbon. In
cleavage of C-C bond and also indicated that reactivity of the
acetyl group is higher than that of the benzoyl group under the
imposed reaction condition. Reason of higher reactivity of acetyl
group in the present study is not clear; it may be due to the
presence
of
oxidizing
agent
(oxone),
this
2,3-
10 dihydroquinazolinone then undergoes oxidation and converted 30 presence of graphitic layers of GO (catalyst) which enhances the
into quinazolin-4(3H)-one (6).
electrophilicity of acetyl group more effectively than benzoyl
group i.e. acetyl group is more exposed than benzoyl group
towards nucleophilic attack under the experimental condition.
When cyclohexane-1,3-dione was treated with anthranilamide in
35 the presence of GO nanosheets (25 mg) in water at 60 °C for 8
h, product 2-(4-oxopentyl)quinazolin-4(3H)-one was generated
in 85% yield (Table 6, entry 2). Interestingly, cyclohexane-1,3-
dione exhibited a higher reactivity than 5,5-dimethylcyclohexane-
1,3-dione (Table 6, entry1). In contrast, cyclopentane-1,3-dione,
40 which contains a five-membered ring, did not give the desired
products when treated with anthranilamide (Table 6, entry 3)
o
even after raising the temperature (100 C) and time period (18
h).
Scheme 1: Plausible reaction pathway for the formation of 2,3-
dihydroquinazolinones and quinazolin-4(3H)-one
15
45
After successful effort to achieve the quinazolin-4(3H)-one from
anthranilamide and aldehyde molecules, we then concentrated to
the formation of the same compound starting from anthranilamide
20 and 1,3-diketones (both cyclic and acyclic) via C-C bond
Table 6 Formation of quinazolin-4(3H)-one derivatives via C-C bond cleavage
50
Sl. No.
1
1,3-diketones/ β-
Product
Yield (%)
69
Time (h)
8
keto ester
7a
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Page 10 of 14
2
3
7
85
7b
ND
18
7c
8a
8b
8c
4
5
6
95
98
80
6
6
6
aReaction conditions: anthranilamide (1 mmol), 1,3 diketone/β-keto ester (1 mmol), GO nanosheets (25 mg), 3 ml H2O at 60 oC for stipulated time. ND-
not detected
GO nanosheets catalyzed condensation reaction of anthranilamide
(1) with 1, 3-diketone (7) involves selective scission of C-C bond,
which follows the course of producing a ketamine intermediate
(II), tautomerization of II generates another intermediate
Experimental Section:
5
Preparation of GO
Natural graphite powder is used for the synthesis of GO
nanosheets. Graphite powder (1000 mg ) and NaNO3 (1000 mg)
20 were added to 35ml of concentrated H2SO4 (98%) under vigorous
stirring in a 250 ml conical flask placed in an ice bath. The whole
mass was converted to black slurry (it takes 2 min), then KMnO4
(5000 mg) was added slowly to the slurry maintaining the
enaminone (III). This enaminone subsequently undergoes
intramolecular nucleophilic addition to generate IV and finally C-
C bond cleavage reaction leads to the generation of the desired
10 product (Scheme 2).
o
reaction temperature between 15 oC and 20 C. After 3 h, the
25 entire system was taken out of the ice bath and diluted with 100
ml water and then further stirred for 3 h at ambient temperature.
200 ml hot water was added to the above reaction mixture
followed by 30% H2O2 until the excess permanganate and
manganese dioxide had been reduced to colourless soluble
30 manganese sulfate. The resultant yellow precipitate was washed
with distilled water several times and then was subjected to
centrifuge to get the pure graphene oxide powder. After repeated
centrifugation, salts and ions results from the oxidation process
can be removed from GO suspensions. The GO nanosheets
35 sample was collected and dried at 60oC for 24 h. The GO
Scheme 2: Plausible reaction pathway for the formation of
quinazolin-4(3H)-one via and oxidant free C-C bond cleavage
15
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nanosheets were characterized using XRD, FTIR, FESEM and
TEM images.
feature of this work and will be considered much efficient
relative to the previously developed methods in terms of product
yield, catalyst loading and mild reaction condition. To the best of
our knowledge this is the first application of a carbocatalyst (GO
General Procedure for the synthesis of 2, 3- 55 nanosheet) for the selective scission of C-C bond. Application of
dihydroquinazolinones:
reusable nanosheets as the catalyst in organic synthesis extends
the scope and may contribute further to progress in chemical
research.
5
Anthranilamide(1) (1 mmol) was added to aldehyde/ketone (2 or
4) derivative (1 mmol) in aqueous medium (3 ml water) followed
by GO nanosheets (25 mg) at room temperature. The mixture was
then stirred for the required period of time (indicated by TLC).
After completion of each reaction, product and the catalysts
Acknowledgement
60 We acknowledge the financial support from University of
Calcutta. N.K. thanks DST, New Delhi, India for DST-Inspire
fellowship. Crystallography was performed at the DST-FIST,
India-funded Single Crystal Diffractometer Facility at the
Department of Chemistry, University of Calcutta.
65
10 separated from reaction system by simple filtration. The crude
product was then dissolved in EtOH (3 ml) and this allows
separation of minute quantity of the catalyst through filtration and
crystallization of the crude product from EtOH furnished pure
compound. All compounds were well characterized by H, 13C
1
15 NMR and FT-IR analysis.
General Procedure for the synthesis of quinazolin-4(3H)-one:
References:
Anthanilamide (1) (1 mmol) was added to aldehyde (2’) (1 mmol)
in aqueous medium (3 ml water) followed by GO nanosheets (25
mg) and oxone (307 mg) at room temperature. The mixture was
20 then stirred for the required period of time (indicated by TLC).
After completion of each reaction, crude product was separated
from reaction system by simple filtration. The crude product was
then dissolved in EtOH (3 ml) and filtered. Finally crystallization
of crude product from EtOH offered the pure compound. All
1. (a) V. Polshettiwar, R. S. Varma, Curr. Opin. Drug Discovery
Dev., 2007, 10, 723; (b) L. I. Belen’kii, V. N. Gramenitskaya, Y.
B
Evdokimenkova, Advances in Heterocyclic Chemistry,
70 Katritzky, A. R., Ed., 2011, 102, 1; (c) L. F. Tietze, A. Modi,
Med. Res. Rev., 2000, 20, 304.
2. (a) Y. S. Sadanadam, R. M. Reddy and A. Bhaskar, Eur. J.
Med. Chem., 1987, 22, 169; (b) G. Bonola and E. Sianesi, J. Med.
Chem., 1970, 13, 329; (c) M. L.Hour, L. Huang, S. Kuo, Y. Xia,
75 K. Bastow, Y. Nakanishi, E. Hamel and K. Lee, J. Med. Chem.,
2000, 43, 4479; (d) R. C. Gupta, R.Nath, K.Shanker, K. P.
Bhargava and K. Kishore, J. Indian Chem. Soc., 1979, 56, 219;
(e) S. E. Lopez, M. E. Rosales, N. Urdaneta, M. V. Gody and J.
E. Charris, J. Chem. Res., 2000, 6, 258; (f) E. Hamel, C. M. Lin,
80 J. Plowman, H. Wang, K. Lee and K. D. Paull, Biochem.
Pharmacol., 1996, 51, 53; (g) V. K. Pandey, S. Tusi, Z. Tusi, R.
Raghubir, M. Dixit, M. N. Joshi and S. K. Bajpai, Indian J.
Chem., 2004, 43, 180; (h) V. K. Srivastava, S. Singh, A. Gulati
and K. Shankar, Indian J. Chem., 1987, 26, 652; (i) N. Pankaj, P.
85 Palit, V. K. Srivastava and K. Shanker, Indian J. Chem., 1989,
28, 745; (j) V. B. Rao, P. Hanumanthu and C. V Ratnam, Indian
J. Chem., Sect. B, 1979, 18, 493; (k) R. P. Maskey, M. Shaaban,
I. G. Wollny and H. J. Laatsch, J. Nat. Prod., 2004, 67, 113.
3. (a) J. Chen, W. Su, H. Wu, M. Liub and C. Jin, Green Chem.,
90 2007, 9, 972; (b) M. Rahman, I. Ling, N. Abdullah, R. Hashim
and A. Hajra, RSC Adv., 2015, 5, 7755; (c) M. Hajjami and B.
Tahmasbi, RSC Adv., 2015, 5, 59194; (d) M. Dabiri, P. Salehi, S.
Otokesh, M. Baghbanzadeh, G. Kozehgary and A. A.
Mohammadi, Tetrahedron Lett., 2005, 46, 6123; (e) J. X. Chen,
95 D. Z. Wu, F. He, M. C. Liu, H. Y. Wu, J. C. Ding and W. K. Su,
Tetrahedron Lett., 2008, 49, 3814; (f) S. Rostamizadeh, A. M.
Amani, G. H Mahdavinia, H. Sepehrian and S. Ebrahimi,
Synthesis, 2010, 1356; (g) V. B. Labade, P. V. Shinde and M. S.
Shingare, Tetrahedron Lett., 2013, 54, 5778; (h) K. M. Khan, S.
100 M.Saad, N. Shaikh, S. Hussain, M. I. Fakhri, S. Perveen, M. Taha
and M I. Choudhary, Bioorg. Med. Chem., 2014, 22, 3449; (i) M.
Prakash and V. Kesavan, Org. Lett., 2012, 14, 1896; (j) L. M.
Wang, L. Hu, J. H. Shao, J. J. Yu and L. J. Zhang, Fluorine
1
25 compounds were well characterized by H, 13C NMR and FT-IR
analysis.
Anthanilamide (1) (1 mmol) was added to 1,3-diketones (7 or 8)
derivative (1 mmol) in aqueous medium (3 ml water) followed by
GO nanosheets (25mg ) at 60 oC. The mixture was then stirred for
30 the required period of time (indicated by TLC). After completion
of each reaction, the crude product mixture was extracted with
ethyl acetate (2x3ml) and finally purified by column
chromatography (eluent- ethyl acetate/petroleum ether: 1:4). All
1
compounds were well characterized by H, 13C NMR and FT-IR
35 analysis.
Conclusion:
We bring to completion developing the catalytic protocol which
is applicable to the formation of both 2,3-dihydroquinazolinones
40 and quinazolin-4(3H)-one. Firstly, cyclo-condensation reaction of
anthranilamide and aldehyde/ketone using GO nanosheet offers
various advantages like operational simplicity, extensive
substrate scope, low catalyst loading, low thermal energy and
high product yield. Use of water as the reaction medium and
45 application of green oxidant make this protocol truly a practical
one in synthetic chemistry and superior to the previously
developed methodologies as it swathes most of the features of
sustainable chemistry. Finally, formation of quinazolin-4(3H)-
one via selective cleavage of C-C bond of 1,3-diketones under
50 metal free and oxidant free condition is the most eye-catching
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Page 12 of 14
Chem., 2008, 129, 1139. (k) A. G. Choghamarani and G. Azadi,
RSC Adv., 2015,5, 9752.
P. Ghosh and A. R. Das, RSC Adv., 2014, 4, 8300; (i) N. Kausar.
P. P. Ghosh. G. Pal, A. R. Das, RSC Adv., 2015, 5, 60199; (j) P.
4. (a) P. T. Anastas and J. C. Warner, Green Chem., Theory and 60 Mukherjee, S. Paul, A. R. Das, New J. Chem., 2015, 39, 9480.
Practice, Oxford University Press, New York, 1998; (b) P. A.
Grieco, Organic Synthesis in Water, Blackie, London, 1998; (c)
U. M. Lindström, Chem. Rev., 2002, 102, 2751; (d) C. J. Li,
Chem. Rev., 2005, 105, 3095; (e) C. J. Li and L. Chen, Chem.
11. (a) D. R. Dreyer and C. W. Bielawski, Chem. Sci., 2011, 2,
1233; (b) S. Navalon, A. Dhakshinamoorthy, M. Alvaro and H.
Garcia, Chem. Rev., 2014, 114, 6179; (c) D. R. Dreyer, H. P. Jia
and C. W. Bielawski, Angew.Chem, Int. Ed., 2010, 49, 6813.
5
Soc. Rev., 2006, 35, 68; (f) C.J. Li and T.H. Chan, 65 12. (a) G. M.Scheuermann, L. Rumi, P. Steurer, W. Bannwarth
Comprehensive Organic Reactions in Aqueous Media, Wiley,
and R.Mülhaupt, J. Am. Chem. Soc., 2009, 131, 8262; (b) N. Li,
Z. Wang, K. Zhao, Z. Shi, S. Xu and Z.Gu, J. Nanosci.
Nanotechnol., 2010, 10, 6748; (c) X. Bin, J. Chen, H. Cao, L.
Chen and, J. Yuan, J. Phys. Chem. Solids, 2009, 70, 1; (d) J. H.
70 Warner, M. H. Ruemmeli, A. Bachmatiuk, M. Wilson and B.
Büchner, ACS Nano, 2010, 4, 470; (e) D. Wang, D. Choi, J. Li, Z.
Yang, Z. Nie, R. Kou, D. Hu, C. Wang, L.V. Saraf, J. Zhang, I.A.
Aksay and J. Liu, ACS Nano, 2009, 3, 907; (f) S. Chen, J. Zhu, X.
Wu, Q. Hanand X. Wang, ACS Nano, 2009, 4, 2822; (g) S. M.
10 New York, 2007; (g) U. M. Lindström, Organic Reactions in
Water: Principles, Strategies and Applications, Blackwell,
Oxford, UK, 2007; (h) A. Chanda and V. V. Fokin, Chem. Rev.,
2009, 109, 725.
5. (a) A. de Meijere, Chem. Rev., 2003, 103, 931; (b) M. E. Boom
15 and D. Milstein, Chem. Rev., 2003, 103, 1759; (c) C. H. Jun,
Chem. Soc. Rev., 2004, 33, 610; (d) Y. J. Park, J. W. Park, C. H.
Jun, Acc. Chem. Res., 2008, 41, 222; (e) M. Tobisu and N.
Chatani, Chem. Soc. Rev., 2008, 37, 300; (f) Y. Horino, Angew. 75 Paek, E. Yoo and I.Honma, Nano Lett., 2009, 9, 72; (h) Qian, S.
Chem. Int. Ed., 2007, 46, 2144; (g) C. Najera and J. M. Sansano,
20 Angew. Chem. Int. Ed., 2009, 48, 2452; (h) S. M. Bonesi and M.
Fagnoni, Chem. Eur. J., 2010, 16, 13572; (i) B. Rybtchinski and
D. Milstein, Angew. Chem. Int. Ed., 1999, 38, 870; (j) R. H.
Luand F. Gao, Mater. Lett., 2011, 65, 56.
13. (a) K. I. Bolotin, K. J. Sikes, Z. Jiang, M. Klima, G.
Fudenberg, J. Hone , P. Kim and H. L. Stormer, Solid State
Commun., 2008, 146, 351; (b) S. V. Morozov, K. S. Novoselov,
Crabtree, Chem. Rev., 1985, 85, 245; (k) C. He, S. Guo, L. Huang 80 M. I. Katsnelson, F. Schedin, D. C. Elias, J. A. Jaszczak and A.
and A. Lei, J. Am. Chem. Soc., 2010, 132, 8273; (l) C. H. Jun,
25 Chem. Soc. Rev.,2004, 33, 610; (m) F. Chen, T. Wang and N.
Jiao, Chem. Rev. 2014, 114, 8613; (n) A. Dermenci, J. W. Coe
and G. Dong, Org. Chem. Front. 2014, 1, 567.
K. Geim, Phys. Rev. Lett., 2008, 100, 016602;(c) A. A. Balandin,
S. Ghosh, W. Z. Bao, I. Calizo, D. Teweldebrhan, F. Miao and C.
N. Lau, Nano Lett., 2008, 8, 902; (d) W. Cai, Y. Zhu, X. Li, R. D.
Piner and R. S. Ruoff, Appl. Phys. Lett., 2009, 95, 123115; (e) H.
6. G. Shen, H. Zhou, P. Du, S Liu, K Zoua and Y. Uozumi, RSC 85 P. Boehm, A. Clauss, G. O. Fischer and U. Hofmann, Z. Anorg.
Adv., 2015, 5, 85646.
30 7. Z. Li, J. Dong, X. Chen, Q. Li, Y. Zhou, and S. F. Yin, J. Org.
Chem., 2015, 80, 9392;
8. X. Sun, X. Li, X. Zhang and L. Wang, Org. Lett.,2014, 16,
2126.
9. (a) A. Kawata, K. Takata, Y. Kuninobu and K. Takai,
35 Angew.Chem., Int. Ed., 2007, 46, 7793; (b) H. Li, W. Li, W. Liu,
Z.He and Z. Li, Angew.Chem., Int. Ed., 2011, 50, 2975; (c) J.
Wang, W. Chen, S. Zuo, L. Liu, X. Zhang and J. Wang, Angew.
Allg. Chem., 1962, 316, 119; (f) H. P. Boehm, R. Setton and E.
Stumpp, Pure Appl. Chem., 1994, 66, 1893; (g) H. P. Boehm, R.
Setton and E. Stumpp, Carbon, 1986, 24, 241;(h) J. Wintterlin
and M. L. Bocquet, Surf. Sci., 2009, 603, 184; (i) A. J.
90 Vanbommel, J. E. Crombeen and A. Vantooren, Surf. Sci., 1975,
48, 463; (j) X. K. Lu, M. F. Yu, H. Huang and R. S. Ruoff,
Nanotechnology 1999, 10, 269; (k) X. K. Lu, H. Huang, N.
Nemchuk and R. S. Ruoff, Appl. Phys. Lett. 1999, 75, 193.
14. (a) W. S. Hummer and R. E. Offeman, J. Am. Chem. Soc.,
Chem., Int. Ed., 2012, 51, 12334; (d) A. Gutierrez-Bonet,A. F. 95 1958, 80, 1339; (b) B. Y. Zhu, W. C. X. Li, J. W. Suk, J. R. Potts
Gaspar and R. Martin, J. Am. Chem. Soc., 2013, 135, 12576; (e)
40 X. Huang, X. Li, M. Zou, S. Song, C. Tang,Y. Yuan and N. Jiao,
J. Am. Chem. Soc., 2014, 136, 14858; (f) N. Ishida, W. Ikemoto
and M. Murakami, J. Am. Chem. Soc., 2014, 136, 5912; (g) H. Li,
and R. S. Ruoff, Adv. Mater., 2010, 22, 3906; (c) L. Shahriary
and A. A. Athawale, Int. J. Energy Environ. Eng., 2014, 2, 58; (d)
I. Roy, A. Bhattacharyya, G. Sarkar, N. R. Saha D. Rana, P. P.
Ghosh, M. Palit, A. R. Das and D. Chattopadhyay, RSC Adv.,
Y. Li, X. S. Zhang, K. Chen, X. Wang and Z. J Shi, J. Am.Chem. 100 2014, 4, 52044.
Soc., 2011, 133, 15244; (h) C. Zhang, P. Feng and N. Jiao, J. Am.
45 Chem. Soc., 2013, 135, 15257; (i) M. S. Mayo, X. Yu, X. Zhou,
X Feng, Y. Yamamoto and M. Bao, Org. Lett., 2014, 16, 764; (j)
Z. Li, J. Dong, X. Chen, Q. Li, Y. Zhou, and S. F. Yin, J. Org.
15. M. Rahman, I. Ling, N. Abdullah, R. Hashim and A. Hajra,
RSC Adv., 2015, 5, 7755.
16. M. Hajjami and B. Tahmasbi, RSC Adv., 2015, 5, 59194.
17. A. G. Choghamarani and G. Azadi, RSC Adv., 2015,5, 9752.
Chem., 2015, 80, 9392; (k) G. Shen, H. Zhou, P. Du, S Liu, K 105 18. J. Chen, W. Su, H. Wu, M. Liub and C. Jin, Green Chem.,
Zoua and Y. Uozumi, RSC Adv., 2015, 5, 85646.
2007, 9, 972;
50 10. P. P. Ghosh and A. R. Das, J. Org. Chem., 2013, 78, 6170; (b)
P. P. Ghosh, G. Pal, S. Paul and A. R. Das, Green Chem., 2012,
14, 2691; (c) S. Paul and A. R. Das, Catal. Sci. Technol., 2012, 2,
19. V. B. Labade, P. V. Shinde and M. S. Shingare, Tetrahedron
Lett., 2013, 54, 5778;
20. A. Rostami and A. Tavakoli, Chin.Chem.Lett., 2011, 22,
1130; (d) K. Pradhan, S. Paul and A. R. Das, Catal. Sci. Technol., 110 1317.
2014, 4, 822; (e) S. Paul, K. Pradhan, S. Ghosh, S. K. De and A.
55 R. Das, Adv. Synth. Catal., 2014, 356, 1301; (g) G. Pal, S. Paul
and A. R. Das, Synthesis, 2013, 45, 191; (h) G. Pal, S. Paul and
A. R. Das, New J. Chem., 2014, 38, 2787; (h) G. Pal, S. Paul, P.
21. (a) K. M. Khan, S. M. Saad, N. Shaikh, S. Hussain, M. I.
Fakhri, S. Perveen, M. Taha and M. I. Choudhary, Bioorg. Med.
Chem., 2014, 22, 3449; (b) H. Hikawa, Y.Ino, H. Suzuki, and Y.
Yokoyama, J. Org. Chem., 2012, 77, 7046; (c) S. M. A. H.
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Siddiki, K. Kon, A. S. Touchy and K. Shimizu, Catal. Sci.
Technol., 2014, 4, 1716.
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Graphical Abstract