Bio-compatible eutectic mixture for multi-component synthesis: A valuable acidic catalyst for synthesis of novel 2,3-dihydroquinazolin-4(1H)-one derivatives

Article abstract of DOI:10.1016/j.catcom.2012.07.020

Novel derivatives of quinazolin-4(1H)-one derivatives were effectively synthesized via one-pot multi-component reaction of isatoic anhydride, aldehyde and aromatic amines using acidic catalyst in methanol. The catalyst, being a deep eutectic mixture of ch

Full text of DOI:10.1016/j.catcom.2012.07.020

Catalysis Communications 27 (2012) 179–183
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Catalysis Communications
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Short Communication
Bio-compatible eutectic mixture for multi-component synthesis: A valuable acidic
catalyst for synthesis of novel 2,3-dihydroquinazolin-4(1H)-one derivatives
⁎
Hyacintha Rennet Lobo, Balvant Shyam Singh, Ganapati Subray Shankarling
Department of Dyestuff Technology, Institute of Chemical Technology, N. P. Marg, Matunga, Mumbai, 400019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 June 2012
Received in revised form 2 July 2012
Accepted 19 July 2012
Available online 27 July 2012
Novel derivatives of quinazolin-4(1H)-one derivatives were effectively synthesized via one-pot multi-component
reaction of isatoic anhydride, aldehyde and aromatic amines using acidic catalyst in methanol. The catalyst, being
a deep eutectic mixture of choline chloride and malonic acid, gave better results than several reported catalysts.
Moreover, such eutectic mixtures are cost-effective, recyclable, non-toxic and bio-degradable. The methodology
was successfully used for incorporating significant phenyl and heterocyclic substitutions at 2,3-positions of
quinazolinone core. In addition, studies related to catalyst screening, substrate variation, recyclability and plausi-
ble mechanism of reaction are also described.
Keywords:
Quinazolinone
Multi-component reaction
Deep eutectic solvent
Choline chloride
Malonic acid
© 2012 Elsevier B.V. All rights reserved.
1. Introduction
Consequently, there is a need for an acidic catalyst that could over-
come the demerits and retain the benefits of the earlier procedures but in
2,3-Dihydroquinazolinones belong to an interesting class of hetero-
cycles that possess a wide range of biological and pharmaceutical activi-
ties [1–3]. Some examples of very significant quinazolinone molecules
include medicinally approved drugs like metolazone, quinethazone,
raltitrexed, fenquizone, as well as bio-active natural products such as
febrifugine and isofebrifugine [4,5]. A potential drug, ZD 9331, is also in
phase II trial for treatment of solid tumors and other neoplasia including
colorectal tumors [6].
Conventionally, 2,3-dihydroquinazolinones have been synthesized
by variety of procedures as stated in literature [7–12]. However,
one-pot synthesis of such significant heterocycles from components
like isatoic anhydride, aldehyde and amines using acidic catalyst or
media has been the subject of interest for many researchers owing to
the growing interest in multi-component reactions (MCRs). MCRs
offer several benefits including low cost, shorter reaction times, high
atom economy, lesser requirement of energy and easier access to di-
verse functional compound libraries.
The catalysts reported for the above stated one-pot procedure in-
clude inorganic catalysts like aluminium tris(dihydrogen phosphate)
[13], silica sulfuric acid [14], alum [15], gallium(III) triflate [16], magnetic
Fe3O4 particles [17], reaction media like acidic ionic liquid [18] and acetic
acid [19]. However, some of these reported procedures hold limitations
like low yields, requirement of high reaction temperature, strong acidic
conditions, use of expensive and toxic catalysts etc.
a simpler and environmentally benign manner. In addition, use of a
non-toxic and bio-degradable catalyst would amplify the aspect of envi-
ronmental benignness of reaction integrated by use of multi-component
route.
In an attempt to achieve this, we have explored the catalytic activity
of deep eutectic solvents (DES) in multi-component synthesis of
quinazolinone derivatives. Deep eutectic solvents are simple ionic mix-
tures derived by combining quaternary ammonium salts, like choline
chloride, with either hydrogen bond donors like urea and glycerol, or
with Lewis acids like zinc chloride. The ability to form a hydrogen
bond with the halide ion leads to a eutectic combination since these
hydrogen-bonding interactions lead to depression in freezing point.
Thus the formation of eutectic is more energetically favored relative to
the lattice energies of the pure constituents [20]. The class of DES
derived from choline chloride is bio-degradable, non-toxic, insensitive
towards moisture, recyclable and cost-effective. This is obvious since
the component choline is a naturally occuring bio-compatible com-
pound and choline chloride is also commercially produced on a large
scale as a chicken feed additive [21]. To add to this, DES also possesses
many positive aspects of ionic liquids like low vapor pressure and low
flammability.
In the past few years, our research group has explored applicability of
deep eutectic mixtures based on choline chloride in several significant
organic transformations [22–25]. We now extend their catalytic use in
multi-component reaction wherein acidic deep eutectic solvent (DES),
prepared from choline chloride and malonic acid was used in one-pot
synthesis of novel 2,3-dihydroquinazolin-4(1H)-one derivatives. Earlier,
this deep eutectic mixture has been used in electrochemistry [26] and
⁎ Corresponding author. Tel.: +91 22 33612708; fax: +91 22 33611020.
E-mail address: gsshankarling@gmail.com (G.S. Shankarling).
1566-7367/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.catcom.2012.07.020

180
H.R. Lobo et al. / Catalysis Communications 27 (2012) 179–183
inorganic synthesis [27]. However, no report related to the catalytic use
CH3
N
of this mixture has been done in multi-component organic synthesis.
This catalyst can be easily prepared from inexpensive starting materials
in addition to being bio-degradable annd recyclable. We also optimized
various parameters of the reaction and studied the recycling of catalyst.
H3C
CH3
HOOC
Cl-
2. Experimental
2.1. Materials and equipments
All the solvents and chemicals were procured from S D fine
chemicals (India) and were used without further purification. The re-
actions were monitored by TLC using 0.25 mm E-Merck silica gel
60F254 precoated plates, which were visualized with UV light. 1H
NMR and 13C-NMR spectrums were recorded on Varian 300 MHz
mercury plus spectrometer, and chemical shifts are expressed in δ
ppm using TMS as an internal standard. Mass spectral data were
obtained with micromass-Q-Tof (YA105) spectrometer. Elemental
analysis was done on Harieus rapid analyzer.
HOOC
OH
Fig. 1. Deep eutectic mixture of choline chloride and malonic acid.
2.2. Preparation of deep eutectic solvent (DES)
The deep eutectic solvents were prepared by combining choline
chloride with various other components like malonic acid, zinc chloride,
urea and glycerol according to the procedures reported in the literature
[20,28,29]. Choline chloride (100 g, 714 mmol) and malonic acid (75 g,
714 mmol) were heated with stirring at 100 °C until a clear solution
began to form. The deep eutectic solvent (Fig. 1) thus formed (175 g,
100%) was cooled and used in reactions without any purification. The
reaction was atom efficient since all the atoms present in the starting
materials were incorporated in the products.
Fig. 2. Studies in recycling of deep eutectic mixture in the multi-component synthesis
of quinazolinone derivative 4a.
2.3. General procedure for deep eutectic solvent catalyzed synthesis of
2,3-disubstituted quinazolinones
A mixture of isatoic anhydride (1 g, 6.1 mmol), aldehyde derivative
(6.1 mmol) and aniline derivative (6.1 mmol) was stirred in methanol
(10 ml) at 65 °C. To this mixture, 20%(v/v) of DES catalyst (2 ml) was
added and the stirring was continued at the same temperature till com-
pletion of reaction. The progress of reaction was monitored on thin
layer chromatography plate. For isolation of product, water was added
to the reaction mixture and the product was extracted with ethyl ace-
tate. The ethylacetate was evaporated using rotary evaporator to give
crude solid which was purified by column chromatography using
hexane: ethyl acetate in 8:2 ratio (v/v). The compounds were charac-
terized using spectroscopic data (FT-IR, Mass, 1H NMR, 13C NMR and
elemental analysis). The deep eutectic solvent was recovered by re-
moving the aqueous layer using rotary evaporator. Even though the
procedure was described with a 1 g scale, it was easily scalable upto
10 g to obtain yields of about 94%. The recovered catalyst obtained
from the scale up batch was re-used upto four runs without any loss
in yields (Fig. 2).
Table 1
Optimization of catalysts in one-pot synthesis of 2-(4-chlorophenyl)-3-(4-methylphenyl)-
2,3-dihydroquinazolin-4(1H)-one.
Sr. no.
Reaction mediuma
DESb Catalyst
Yield (%)c
1
2
Methanol
Methanol
–
Traces
83
87
88
94
92
20
15
45
5% DES (CHCl: malonic acid)
10% DES (CHCl: malonic acid)
15% DES (CHCl: malonic acid)
20% DES (CHCl: malonic acid)
25% DES (CHCl: malonic acid)
20% DES (CHCl:glycerol)
20% DES (CHCl:urea)
3
4
5
Methanol
Methanol
Methanol
20% DES (CHCl:Zinc chloride)
a
Reaction conditions: isatoic anhydride (1 g, 6.1 mmol), 4-chlorobenzaldehyde
(0.87 g, 6.1 mmol), 4-methylaniline (0.67 g, 6.1 mmol), DES catalyst(% v/v), methanol
(10 vol), reaction time=2 h; Reaction temperature=65 °C.
b
DES: deep eutectic solvent.
Isolated yields.
c
Scheme 1. Synthesis of novel quinazolinone derivatives via multi-component reaction by the catalytic activity of acidic deep eutectic mixture.

H.R. Lobo et al. / Catalysis Communications 27 (2012) 179–183
181
2.3.1. Spectral data of representative compound
3. Results and discussion
2-(4-chlorophenyl)-3-(4-methylphenyl)-2,3-dihydroquinazolin-4
(1H)-one (Entry 4a, Table 2): (2.0 g , 94%, solid, m.p. 270–274 °C); FT-IR
3.1. Influence of type and quantity of catalyst on MCR yield
ν=3299, 1633, 1607, 1508, 1484, 1385, 1315, 1086, 820 cm-1 1H NMR
;
(300 MHz, CDCl3): δ 2.30 (s, –CH3, 3H), 6.10 (s, –CH, 1H), 6.60–8.0 (m,
Ar-H, 12H); 13C NMR (300 MHz): δ 21.1, 74.1, 115.0, 119.9, 126.8,
128.3, 128.9, 129.0, 129.1, 129.8, 131.6, 134.0, 136.9, 137.8, 138.6, 145.1;
EIMS m/z=349.1, C21H17ClN2O, calculated m/z: 348.8; Anal. Calcd for
C21H17ClN2O: C,72.31; H, 4.91; N, 8.03. Found: C, 71.81; H, 4.95; N, 8.27.
We initially screened various deep eutectic mixtures as catalyst in
methanolic media to derive the best outcome. The deep eutectic solvents
generated from glycerol or urea gave very less yields owing to their lesser
acidity than DES made from acidic components. However, the eutectic
mixture of choline chloride: malonic acid gave best results amongst all
Table 2
One pot synthesis of 2,3-disubstituted-2,3-dihydroquinazolin-4(1H)-ones by reaction of isatoic anhydride with primary amines and aldehydes.
Entry no.
1.
Aldehydes
Amines
Productsa
Time (h)
2
Yields (%)b
94
(4a)
(4b)
2.
3.
2.5
92
89
3
(4c)
4.
3.5
80
(4d)
(4e)
(4f)
5.
6.
7.
2.5
2.5
3
95
85
83
(4g)
8.
2.5
92
89
(4h)
(4i)
9.
3
a
Reaction conditions: isatoic anhydride (1 g, 6.1 mmol), aldehyde derivative (6.1 mmol), aniline derivative (6.1 mmol), 20% DES catalyst (2 ml) in methanol (10 ml), reaction temp=65 °C.
Isolated yields.
b

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H.R. Lobo et al. / Catalysis Communications 27 (2012) 179–183
Scheme 2. Proposed reaction mechanism in synthesis of quinazolinone derivatives using acidic deep eutectic solvent as catalyst.
other eutectic mixtures (Table 1). The optimization for quantity of cata-
lyst suggested 20% (v/v) of DES catalyst in methanol as the optimum
quantity for effective results.
4. Conclusion
In conclusion, we prepared novel derivatives of quinazolinone
with varied substitutions at 2,3 positions by using bio-degradable
acidic deep eutectic catalyst in a one pot, multi-component synthesis.
The products, involving different aromatic and heteroaromatic substi-
tutions like quinaldine, indole, pyridine, thiazole and furan moeities,
were prepared in excellent yields. The highlights of the catalyst in-
cludes its bio-degradability, non-toxic nature, ease in preparation
and requirement of inexpensive starting materials. The catalyst was
also easily recyclable with no loss in yields at least upto five runs.
3.2. Multi-component synthesis of quinazolinone derivatives by use of
functionalized substrates
A variety of aromatic as well as heteroaromatic aldehydes and amines
underwent three component condensation with isatoic anhydride by
this procedure to produce several novel 2,3-dihydroquinazolin-4(1H)-
one derivatives (Scheme 1). The results are summarized in Table 2. The
aromatic amines selected include phenyl substituted amines, 2-methyl
quinaldine and 2-amino thiazole. The aldehydes involved substituted
benzaldehydes, pyridine-2-aldehyde and indole-3-aldehyde. The method
showed good tolerance towards various functional groups including
nitro, chloro and methoxy. The reaction gave high yields of product.
Acknowledgments
Authors are thankful to UGC-CAS for providing fellowship and SAIF
IIT-Bombay, 1H-NMR, 13C-NMR, elemental analysis and Mass spectra.
Appendix A. Supplementary data
3.3. Scale-up batch and recyclability studies
Supplementary data to this article can be found online at http://
dx.doi.org/10.1016/j.catcom.2012.07.020.
The batch of reaction between isatoic anhydride, 4-chlorobenzal-
dehyde and 4-methylaniline was scaled up to understand the func-
tioning of the method at larger scale. The deep eutectic mixture
recovered from the scale-up batch was re-used for further runs of
recycling studies (Fig. 1). The recovery was very simple involving
evaporation of the methanol and water after isolation of product by
extraction. The deep eutectic solvent was reused without any loss in
activity till five consecutive runs.
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mechanism, has been confirmed experimentally by earlier reports [15].

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