An Efficient, Convenient, and Solvent-Free Synthesis of 2,3-Dihydroquinazolin-4(1 H)-ones Using Montmorillonite-KSF Clay as a Heterogeneous Catalyst

Full text of DOI:10.1080/00304948.2018.1462058

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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An Efficient, Convenient, and Solvent-Free
Synthesis of 2,3-Dihydroquinazolin-4(1 H)-
ones Using Montmorillonite-KSF Clay as a
Heterogeneous Catalyst
Sunil U. Tekale, Shivaji B. Munde, Sushama S. Kauthale & Rajendra P. Pawar
To cite this article: Sunil U. Tekale, Shivaji B. Munde, Sushama S. Kauthale & Rajendra P. Pawar
(2018) An Efficient, Convenient, and Solvent-Free Synthesis of 2,3-Dihydroquinazolin-4(1 H)-
ones Using Montmorillonite-KSF Clay as a Heterogeneous Catalyst, Organic Preparations and
Procedures International, 50:3, 314-322, DOI: 10.1080/00304948.2018.1462058
To link to this article: https://doi.org/10.1080/00304948.2018.1462058
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Organic Preparations and Procedures International, 50:314–322, 2018
Copyright Ó Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2018.1462058
An Efficient, Convenient, and Solvent-Free Synthesis
of 2,3-Dihydroquinazolin-4(1 H)-ones Using
Montmorillonite-KSF Clay as a Heterogeneous
Catalyst
Sunil U. Tekale,1 Shivaji B. Munde,2 Sushama S. Kauthale,1
and Rajendra P. Pawar1
1Department of Chemistry, Deogiri College, Station Road, Aurangabad (MS),
India 431005
2Department of Chemistry, Shri Muktanand College, Gangapur (MS), India
431109
Quinazolinones have a unique position in pharmaceutical and medicinal chemistry due
their diversified biological activities.1 Quinazolinone derivatives act as the building
blocks of more than 150 natural products2 and many commercially marketed drugs,
including Cloroqualone, Afloqualone, and Quinethazone. Cloroqualone is a drug with
sedative and antitussive properties. Afloqualone is a muscle-relaxant and Quinethazone is
widely used in the treatment of hypertension. Besides this, quinazolinones are well recog-
nized for antibacterial,3 antifungal,4 cytotoxic,5 anticancer,6 anti-inflammatory,7 antima-
larial,8 anticonvulsant,9 antidepressant,10 antioxidant,11 activities. On account of their
therapeutic potential and wide spectrum of biological activities, quinazolinones have
attracted the attention of medicinal and synthetic organic chemists. The development of
new synthetic strategies for the synthesis of quinazolinones is thus of considerable
interest.
A literature survey reveals that the synthesis of quinazolinones can be achieved by
the reaction of isatoic anhydride, ammonium acetate or amine and aldehyde using cata-
lysts and reagents such as thiamine hydrochloride,12 b-cyclodextrin,13 Cu(NO3)2.3H2O,14
L-Proline,15 Preyssler nanoparticles,16 sulfonated porous carbon,17 silica supported zinc
21
(II) chloride,18 2,4,6-trichloro[1,3,5]triazine,19 acetic acid,20 ionic liquids
sound irradiation.22
and ultra-
Solvent-free or solid state reactions reduce environmental pollution and lower han-
dling costs due to their operational simplicity and ease of work up procedures.23 These
reactions can be performed by using the reactants alone or using clays, silica, alumina or
other catalytic materials. Multicomponent reactions under solvent-free conditions consti-
tute an important tool for efficient functional group transformations.24
Received May 1, 2017; in final form November 20, 2017.
Address correspondence to Rajendra Pawar, Department of Chemistry, Deogiri College,
Station Road, Aurangabad (MS), India 431 005. E-mail: rppawar@yahoo.com
Color versions of one or more figures in this article can be found online at
www.tandfonline.com/uopp.
314

2,3-Dihydroquinazolin-4(1 H)-ones
315
Clays are natural inorganic aluminosilicates containing both Lewis and Bronsted acidic
sites and serve as environmentally benign reusable heterogeneous catalysts and substi-
tutes for corrosive liquid acids in both organic and inorganic transformations.25 Bronsted
acidic sites are associated within the interlamellar regions and Lewis sites are associated
with edges. Clays are insoluble in organic solvents and can be easily separated from reac-
tion mixtures and can be recycled. Chemically modified clays are useful as cost-effective
materials. Clay catalysis is highly desirable and an integral part of green chemistry due to
cheapness, non-toxicity, non-corrosiveness, and its economical, eco-friendly and recycla-
ble nature.
Among the clays, montmorillonite clay catalyzed reactions afford high yields with
good selectivity. Montmorillonite-KSF has a high surface area (130 m2/ g) and low pH
(1–2). It has emerged as an inorganic, water stable and reusable solid Lewis acid hetero-
geneous catalyst. It has been successfully used for Diels-Alder reactions, Biginelli reac-
tions, Fischer indole cyclizations, Heck vinylations, Pinacol coupling reactions and
Pechmann condensations.26
In the present study, we report an efficient one-pot three-component synthesis of
2,3ÀdihydroquinazolinÀ4(1 H)Àones by the reaction of isatoic anhydride, ammonium
acetate or amine and aldehyde under solvent free conditions using montmorillonite-KSF
clay as a reusable heterogeneous catalyst (Scheme 1).
O
O
R1
R
NH4OAc
or
N
O
Montmorillonite KSF (10 wt%)
solvent-free, 120 oC, 2-5 h
R
CHO
R1NH2
N
H
N
H
O
R1 = H, aryl
Scheme 1 Synthesis of 2,3-dihydroquinazolin-4(1H)-ones using Montmorillonite-KSF.
To optimize the reaction conditions and parameters, the reaction of benzaldehyde, ammo-
nium acetate and isatoic anhydride using 10 wt% of montmorillonite-KSF catalyst was
chosen as a model condensation reaction. A literature survey revealed that ethanol is the
most commonly employed solvent for this transformation. Initially we tried the reaction
in ethanol at room temperature which was found to be sluggish. When the reaction mix-
ture was refluxed in ethanol, it required a long time for completion (5 h) affording the
product in low yield (Table 1).
Then the model reaction was tried in several solvents having boiling points near
80ꢀC, such as acetonitrile, 1,2-dichloroethane (DCE) and ethyl acetate. The yield was
very poor in ethyl acetate, low in DCE and comparatively better in acetonitrile after 5 h.
We then raised the reaction temperature to 100ꢀC, using dioxane or dioxane:water (1:1)
as solvent for the model reaction, but still poor results were obtained. In summary, etha-
nol was found to be better but required 5 h for completion and the yield of the product
was not more than 75%. Finally we gradually raised the reaction temperature above
100ꢀC under solvent free conditions and found that the reaction was complete at 120ꢀC
within 2 h. Under solvent-free conditions, stirring of the reaction mass becomes difficult
but the rise in temperature to 120ꢀC facilitates the transformation by melting of all the
contents except the montmorillonite-KSF clay.
Next, the model reaction was optimized with varying concentrations of the catalyst
from 10 to 40 wt%. It was found that 10 wt% concentration of the catalyst was sufficient
under solvent free conditions at 120ꢀC.

316
Pawar et al.
Table 1
Effect of Various Solvents on the Synthesis of 2,3ÀdihydroquinazolinÀ4-(1 H)Àones
Entry
Solvent
Temperature (ꢀC)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
10
Ethanol
Ethanol
r.t.
24 h
5 h
8 h
8 h
8 h
5 h
5 h
5 h
2.5 h
2 h
20
75
60
28
87
20
30
27
82
87
reflux
reflux
reflux
reflux
reflux
reflux
reflux
100
1,2-Dichloroethane
Ethyl acetate
Acetonitrile
Dioxane
Dioxane: water (1:1)
Water
Solvent-free
Solvent-free
120
Reaction conditions: Isatoic anhydride (1mmol), benzaldehyde (1 mmol), ammonium acetate
(1.5 mmol) and montmorillonite-KSF (10 wt %).
To check the feasibility, generality and substrate scope of this transformation, several
aldehydes were treated with isatoic anhydride, ammonium acetate and montmorillonite-
KSF under solvent-free conditions, resulting in very good yields of the desired products.
The scope and utility of the one-pot three-component condensation reaction was extended
by replacing ammonium acetate with different aromatic amines. However, in this case,
comparatively longer reaction times were required, perhaps due to steric hindrance during
ring closure. From Table 2, it is clear that the substituents on the aromatic rings of the
aldehydes or amines had no major effect on the reaction yields and the yields were uni-
formly very good.
After completion of the reaction, as monitored by thin layer chromatography, the
reaction mass was diluted with hot ethanol and filtered off to separate the catalyst.
The catalyst was washed several times with hot ethanol, the combined filtrates were
concentrated on a rotary evaporator to get the crude product which was recrystal-
lized with hot ethanol to afford the pure 2, 3ÀdihydroquinazolinÀ4(1 H)-ones. The
recovered catalyst was dried in an electric furnace at 120ꢀC for 1 h and recycled
(See Experimental Section). The products were identified by matching their melting
points to those of the literature and analysis of spectral data. The present method
constitutes an efficient one pot three component synthesis of 2,3-dihydroquinazolin-4
(1 H)-ones. Being solvent-free, the present protocol constitutes a valuable addition
to the existing literature methods for the synthesis of dihydroquinazolin-4(1 H)-ones
avoiding the use of solvents which is beneficial in terms of green chemistry as well
as economical perspectives.
Experimental Section
Chemicals used were SD Fine or Sigma Aldrich made and used without further
purification. Progress of the reaction was monitored using thin layer chromatography
(30% ethyl acetate: n-hexane) on silica gel precoated aluminum plates. Products were
characterized by spectroscopic data (1H NMR, 13C NMR, EI-MS and IR spectra) and
comparison of their physical constants with the literature values. NMR spectra of the
products were scanned on Varian 400 MHz spectrophotometer in DMSO-d6 solvent using

2,3-Dihydroquinazolin-4(1 H)-ones
317

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Pawar et al.

2,3-Dihydroquinazolin-4(1 H)-ones
319

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Pawar et al.

2,3-Dihydroquinazolin-4(1 H)-ones
321
Table 3
Recycling Study of Catalyst
Run
Fresh
87
I
II
III
75
IV
69
Yield (%)
84
79
tetramethylsilane (TMS) as an internal standard. Coupling constants were in the range of
5–8 Hz. IR spectra were recorded on a Bruker Vector 22 FTIR spectrophotometer.
General Procedure for the Motmorillonite KSF Catalyzed Solvent-free Synthesis of 2,
3-dihydroquinazolin-4(1 H)-ones
Montmorillonite-KSF clay catalyst was activated by heating in electric oven at 120ꢀC for 1 h
prior to the reaction to remove traces of moisture. A mixture of isatoic anhydride (2 mmol),
ammonium acetate (3 mmol) or amine (2 mmol) and montmorillonite KSF (10 wt%) was
stirred and heated at 120ꢀC for 30 minutes. To this mixture an aldehyde (2 mmol) was added
and the contents were heated under stirring for the appropriate time, as specified in Table 2.
After completion of the reaction as monitored by TLC, the reaction mass was diluted with hot
ethanol (10 mL) and filtered to separate the catalyst, which was washed on the filter several
times with hot ethanol (3 £ 5 mL). The combined filtrates were concentrated on a rotary evap-
orator to get the crude product which was further purified by recrystallization from ethanol.
Representative Spectroscopic Data
2-(4-Chlorophenyl)-2,3-dihydroquinazolin-4(1 H)-one (Table 2, Entry 2). White pow-
der; 1H NMR (400 MHz, DMSO-d6): d ppm 5.75 (s, 1 H), 6.7 (d, 2 H), 7.19 (s, 1 H), 7.21
(t, 1 H), 7.5 (dd, 4 H), 7.6 (d, 1 H), 8.39 (s, 1 H); 13C NMR (100 MHz, DMSO-d6): d ppm
65.77, 78.68, 79.34, 114.88, 117.25, 127.33, 128.25, 132.99, 133.33, 140.57, 147.59,
163.51; EI-MS: m/z D 259 (MC1)C; IR (neat) cm¡1 3298, 2926, 1633, 1508, 1415.
2-(4-Chlorophenyl)-2, 3-dihydro-3-phenylquinazolin-4(1 H)-one (Table 2, Entry 11).
1
White solid; H NMR (DMSO-d6, 400 MHz) d ppm 6.3 (s, 1 H), 7.75 (m, 2 H), 7.1–7.4
13
(m, 10 H), 7.7 (s, 1 H), 7.75 (d, 1 H); C NMR (DMSO-d6, 100 MHz) d ppm 72.07,
114.88, 115.33, 117.75, 126.26, 128.06, 128.51, 128.65, 132.99, 133.86, 139.63, 140.62,
146.40, 162.22; EI-MS 333.2 (M-1) (Negative mode), 335.2 (MC1) (Positive mode); IR
(neat) cm¡1 3298, 2926, 1633, 1612, 1486, 1392, 787.
The recovered catalyst was observed to work well up to the third recycle on the
model condensation reaction (Table 3). Some decrease in the yield of product after the
third recycle is due to loss of catalyst during recovery.
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