Cp2ZrCl2-catalyzed synthesis of 2-substituted quinozolin-4(3H)-ones

Article abstract of DOI:10.1002/aoc.3013

Zirconocene dichloride (Cp₂ZrCl₂) in the presence of DMF was found to be a highly efficient catalyst for the synthesis of structurally diverse 2-substituted quinozolin-4(3H)-ones by reaction of anthranilimide with a wide range of aryl aldehydes. Copyright

Full text of DOI:10.1002/aoc.3013

Full Paper
Received: 20 February 2013
Revised: 24 April 2013
Accepted: 30 April 2013
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/aoc.3013
Cp2ZrCl2-catalyzed synthesis of 2-substituted
quinozolin-4(3H)-ones
Jagannath Jadhav, Sharanabasappa Khanapure, Rajashri Salunkhe and
Gajanan Rashinkar*
Zirconocene dichloride (Cp2ZrCl2) in the presence of DMF was found to be a highly efficient catalyst for the synthesis of
structurally diverse 2-substituted quinozolin-4(3H)-ones by reaction of anthranilimide with a wide range of aryl aldehydes.
Copyright © 2013 John Wiley & Sons, Ltd.
Keywords: zirconocene dichloride; Lewis acid; quinozolin-4(3H)-ones
aldehydes with anthranilamide is one of the most classical and
established methods for the synthesis of quinozolin-4(3H)-ones.
Introduction
Organozirconocenes have become useful scaffolds in synthetic
organic chemistry since the pioneering work of Schwartz[1] and
Negeshi.[2] Among them, the cationic zirconocene compounds have
been used as valuable reagents for mediating synthetically important
transformations.[3] Zirconocene dichloride (Cp2ZrCl2) and its
derivatives constitute an important class of cationic zirconocene
complexes that are regarded as stable, non-hazardous and ideal
catalysts.[4] The catalytic activity of Cp2ZrCl2 is attributed to its weak
acidity. Cp2ZrCl2 has been an extensively used catalyst in
polymerization reactions.[5] However, despite the impressive catalytic
potential of Cp2ZrCl2, its utility in organic synthesis is only
sporadically demonstrated. Some of the catalytic processes initiated
by Cp2ZrCl2 include synthesis of multi-substitutedvinyl silanes,[6] bis
(indolyl) methanes[7] and cyclobutenyl phosphaonates.[8] Cp2ZrCl2
has also been reported to catalyze acetylation of phenols/alcohols/
amines,[9] coupling of terminal alkynes as well as intramolecular
coupling of imines and alkynes[10] and Refortmastky and Barbier
reactions.[11] To tap the barely exploited potential of Cp2ZrCl2 in
organic synthesis, we sought to explore the catalytic potential of
Cp2ZrCl2 in the synthesis of heterocyclic compounds with a high
therapeutic value.
Although several catalysts have been used to promote this
transformation,[24] there is still scope of improvement, especially
towards developing a facile approach using highly an active and
efficient catalyst.
In continuation of our work directed towards the use of
organometallic catalysts in organic synthesis,[25] we wish to report
herein the synthesis of 2-substituted quinozolin-4(3H)-ones by
reaction of anthranilimide with aryl aldehydes using Cp2ZrCl2 as a
catalyst (Scheme 1).
Results and Discussion
Benzaldehyde and anthranilimide were chosen as model substrates
for optimization of the reaction conditions. The initial effort
was directed towards optimization of catalyst loading. The various
quantities of Cp2ZrCl2 were assessed for the model reaction using
DMF as solvent at 100 ꢀC. The model reaction was restrained by
the use of 5 mol% of catalyst. The 10 mol% concentration of catalyst
promoted the reaction, furnishing an excellent yield of
corresponding product (Table 1, entry 6). The use of excess
amounts of the catalyst (15 and 20 mol%) did not have a
marked influence on the yield of the product (Table 1, entries
7 and 8). It is noteworthy that in a blank experiment no
reaction was observed under similar reaction conditions in
the absence of Cp2ZrCl2. The influence of the solvent on
model reaction was also investigated. While polar protic
solvents such as methanol and ethanol afforded the desired
product in lesser yield (Table 1, entries 1 and 5), polar aprotic
solvents such as THF, acetonitrile and 1,4-dioxane afforded
the anticipated product in moderate yield (Table 1, entries
2–4). In DMF, the conversion of anthranilimide into
Quinozolin-4(3H)-ones have attracted attention as an important
class of heterocyclic compounds in the field of drugs and pharma-
ceuticals.[12] The inclusion of this skeleton in more complex struc-
tures has led to a diverse range of bioactive molecules which
exhibits a wide range of pharmacological properties such as
antiviral,[13] antibacterial,[14,15] antitumor,[16] antimalerial,[17]
antihypertensive[18] and anti-inflammatory activities.[19] Moreover,
many of their derivatives are selective COX II inhibitors as well as
inhibitors of derived growth factor receptor phosphorylation.[20]
Owing to their therapeutic efficacy, development of facile protocols
for the synthesis of quinozolin-4(3H)-ones with a diverse structural
pattern has been a subject of immense interest to organic
chemists. The synthetic strategies employed for the construction
of 4(3H)-quinazolinone skeletons include cyclization of o-
acylaminobenzamides,[21] amidation of 2-aminobenzonitrile
followed by oxidative ring closure[16,22] and Pd-catalyzed
heterocyclization of nitroarenes.[23] However, the reaction of aryl
*
Correspondence to: G. Rashinkar, Department of Chemistry, Shivaji University,
Kolhapur, 416004 MS, India. E-mail: gsr_chem@unishivaji.ac.in
Department of Chemistry, Shivaji University, Kolhapur, 416004, MS, India
Appl. Organometal. Chem. 2013, 27, 486–488
Copyright © 2013 John Wiley & Sons, Ltd.

Cp2ZrCl2-catalyzed synthesis of 2-substituted quinozolin-4(3H)-ones
Table 2. Cp2ZrCl2-catalyzed synthesis of 2-substituted quinozolin-4
(3H)-onesa
Scheme 1. Synthesis of 2-substituted quinozolin-4(3H)-ones.
quinozolin-4(3H)-one was found to be exclusive. In the course
of our study, we found that temperature plays a very crucial
role in bringing out the desired transformation (Table 1, en-
tries 6–8). The maximum yield of desired product was
obtained by employing the reaction at 100 ꢀC in DMF. From
the above observations we inferred that reaction of benzalde-
hyde (1.0 mmol) and anthranilimide (1.0 mmol) with 10 mol%
of Cp2ZrCl2 in DMF as the solvent at 100 ꢀC would be the ideal
condition for the reaction.
[ref.]
Entry
Ar
Productb
Time (h)
Yieldc (%)
1
Ph
3a[26a]
3b[26a]
3c[26a]
3d[26a]
3e[26b]
3f[26b]
3g[22a]
3h[24a]
3i[26a]
3i[26a]
3k[26a]
3l[26a]
—
8
7
85
80
78
82
76
75
82
80
60
46
39
68
—
2
p-MePh
3
p-OMePh
p-ClPh
7
4
4
5
p-FPh
4
6
p-BrPh
6
Having established the optimized condition, a series of
quinozolin-4(3H)-ones were prepared by reacting anthranilimide
with a wide range of aryl aldehydes with diverse substituent pat-
terns. The results of reactions are summarized in Table 2. The re-
actions proceeded smoothly in all cases, affording the desired
products in good yields. Several sensitive functionalities such as
OMe, Cl, F, Br and NO2 (Table 2, entries 3–8) on the aryl aldehyde
nucleus were unaffected under the present reaction conditions.
The reactions of heteroaromatic aldehydes (Table 2, entries 9–
11) gave comparatively poor yields, which may be rationalized
on the basis of participation of heteroatom in the formation of
stable complex with Zr, which greatly reduces the catalytic activ-
ity. 9-Anthracenealdehyde was found to be inactive under opti-
mized reaction conditions, presumably due to steric hindrance
(Table 2, entry 13). All the synthesized quinozolin-4(3H)-ones
are known compounds and were characterized by comparing
7
m-NO2Ph
p-NO2Ph
3-Pyridine
2-Furan
3
8
2
9
2
10
11
12
13
4
2-Thiophene
2-Naphthalene
9-Anthracene
4
6
10
aAnthranilimide (1 mmol), aromatic aldehyde (1 mmol) and
zirconocene dichloride(10 mol%) in DMF (5 ml) were stirred at a
temperature of 100 ꢀC.
bAll products were characterized by IR, 1H NMR, 13C NMR and
mass spectrometry.
cIsolated yields after chromatography.
1
their melting point, IR, H NMR, 13C NMR and mass spectra with
those found in the literature.[24,26]
plausible mechanism showing the catalytic role of Cp2ZrCl2 is
depicted in Scheme 2. Initially, Zr of Cp2ZrCl2 activates carbonyl
group by coordinating with carbonyl oxygen.[11] This facilitates
nucleophilic attack of the amino group on the carbonyl carbon
leading to the formation of intermediate A. The catalyst further
activates an imine[27] intermediate (B), thereby leading to
cyclization, which furnishes the desired product.
The catalytic role of Cp2ZrCl2 in the formation of quinozolin-4
(3H)-ones from anthranilimide was evident from the observation
that its presence is necessary for the occurrence of reaction. A
Table 1. Optimization studies on cyclocondensation of
anthranilimide and benzaldehydea
In conclusion, we have developed a simple and efficient
methodology to synthesize quinozolin-4(3H)-one derivatives using
Cp2ZrCl2 as a catalyst. The methodology has much scope for exten-
sion to a variety of substrates with various functional groups. The
Entry
Solvent
Catalyst Temperature
Time
(h)
Yieldb
(%)
(mol %)
(
ꢀC)
1.
2.
3.
4.
5.
6.
7.
8.
Methanol
THF
10
10
10
10
10
10
15
20
65
70
70
80
80
28
20
22
28
17
8
26
32
40
54
67
85
86
88
Acetonitrile
1,4 Dioxane
Ethanol
DMF
100
100
100
DMF
8
DMF
7
aAnthranilimide (1 mmol), benzaldehyde (1 mmol) and zirconocene
dichloride in 5 ml of solvent were stirred at the appropriate
temperature.
bIsolated yields after chromatography.
Scheme 2. A proposed mechanism for the synthesis of quinozolin-4(3H)-
ones using Cp2ZrCl2.
Appl. Organometal. Chem. 2013, 27, 486–488
Copyright © 2013 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

[13] M. Schleiss, J. Eickhoff, S. Auerochs, M. Leis, S. Abele, S. Rechter,
Y. Choi, J. Anderson, G. Scott, W. Rawlinson, D. Michel, S.
Ensminger, B. Klebl, T. Stamminger, M. Marschall, Antiviral Res.
2008, 79, 49.
easy formation of substituted quinozolin-4(3H)-ones from inexpen-
sive starting materials makes this process a viable alternative to
more traditional syntheses of quinozolin-4(3H)-ones.
[14] L. Kubicova, P. Kudelova, H. Dostal, K. Waisser, Folia Pharm. Univ.
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[15] J. Hanusek, J. Chemicke Listy. 2001, 95, 811.
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Experimental
General Procedure for Synthesis of Quinozolin-4(3H)-ones
[17] K. Haruhisa, Y. Keisuke, H. Seiko, H. Shingo, K. Ryota, H. Norimitsu, M.
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A mixture of anthranilimide (1mmol), aromatic aldehyde (1mmol)
and zirconocene dichloride in DMF (5ml) were stirred at an
appropriate temperature. After completion of reaction, as indicated
by thin-layer chromatography, the reaction mixture was quenched
in cold water. The obtained crude solid was filtered and purified by
column chromatography on silica gel (Merck; 60-120 mesh, ethyl
acetate:hexane) to afford the pure product.
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Appl. Organometal. Chem. 2013, 27, 486–488