Facile method for the combinatorial synthesis of 2,2-Disubstituted Quinazolin-4(1 H)-one derivatives catalyzed by iodine in ionic liquids

Article abstract of DOI:10.1021/cc900174p

A mild and facile method for the combinatorial synthesis of quinazolin-4-(1H)-one derivatives, containing simple 2,2-disubstituted quinazolin-4-(1H)-ones, spirocyclic quinazolin-4-(1H)-ones, spiro-heterocyclic quinazolin-4-(1H)-ones, and dispirocyclic quinazolin-4-(1H)-ones, is described, which results in high yields by using ionic liquids as green media. The method involves the reaction of 2-aminobenzamides with various ketones catalyzed by iodine and provides new quinazolin-4-(1H)-one library for biomedical screening.

Full text of DOI:10.1021/cc900174p

J. Comb. Chem. 2010, 12, 417–421
417
Facile Method for the Combinatorial Synthesis of 2,2-Disubstituted
Quinazolin-4(1H)-one Derivatives Catalyzed by Iodine in Ionic Liquids
Xiang-Shan Wang,* Ke Yang, Jie Zhou, and Shu-Jiang Tu
School of Chemistry and Chemical Engineering, Xuzhou Normal UniVersity, The Key Laboratory of
Biotechnology on Medical Plant, Xuzhou Jiangsu 221116, P. R. China
ReceiVed NoVember 8, 2009
A mild and facile method for the combinatorial synthesis of quinazolin-4-(1H)-one derivatives, containing
simple 2,2-disubstituted quinazolin-4-(1H)-ones, spirocyclic quinazolin-4-(1H)-ones, spiro-heterocyclic
quinazolin-4-(1H)-ones, and dispirocyclic quinazolin-4-(1H)-ones, is described, which results in high yields
by using ionic liquids as green media. The method involves the reaction of 2-aminobenzamides with various
ketones catalyzed by iodine and provides new quinazolin-4-(1H)-one library for biomedical screening.
1. Introduction
solvent catalyzed by Alum or p-TSA.15 These reported
methods involve various disadvantages, such as low yields,
prolonged reaction times, and the use of toxic organic
reagents and catalysts. So, development of a facile and green
method to synthesize 2,2-disubstituted quinazoline appears
urgently necessary.
Room temperature ionic liquids (RTILs), especially those
based on the 1-N-alkyl-3-methyl imidazolium cation, have
shown great promise as attractive alternatives to conventional
solvents.1 The distinctive property of room temperature ionic
liquids is that they have essentially no vapor pressure, which
makes them optimal replacements for the volatile organic
solvents traditionally used as industrial solvents. Another
feature of ionic liquid is its ability to be reused many times.
Because of these advantages, ionic liquids have made
significant contributions to green chemistry and have been
used widely as reaction medium in organic chemistry,2 as
well as in combinatorial chemistry.3
Quinazoline and its derivatives have recently been evalu-
ated as antagonists of various biological receptors, such as
5-HT5A related diseases,4 calcitonin gene-related peptide,5
and vasopressin V3 receptors.6 2-Substituted quinazolines
have also been tested for their potential activities, for
example, antiinflammatory,7 antihypertensive,8 anticancer,9
antitumor,10 and antibacterial activity.11 Hence, the synthesis
of quinazoline derivatives is currently of great interest in
organic synthesis. Previous methods reported for the syn-
thesis of 2-arylquinazoline were based on 2-aminobenzamide
with aromatic aldehyde catalyzed by NH4Cl, AlCl3/ZnCl2,
p-TSA, other Lewis acids, and asymmetric Bronsted acids12
or one-pot condensation of isatoic anhydride and amines with
aldehydes in organic solvent.13 In addition, using 2-nitroben-
zamide and aldehyde or ketone as reactants induced by low-
valence titanium was also reported as a facile process to
synthesize quinazoline derivatives in the literature.14
To the best of our knowledge, most of above-mentioned
studies on the synthesis of quinazolines are focused on
2-monosubstituted ones using various aldehydes as reactants.
Few examples has been given to obtain double substituents
on the 2-position in quinazoline moieties from ketones.
Furthermore, the known methods are described in organic
Over the past few years, molecular iodine (I2) has emerged
as a powerful catalyst for various organic transformations
to afford the products in good to excellent yields. Because
of several advantages, such as it being inexpensive, nontoxic,
and eco-friendly, iodine has been used as a catalyst in the
investigation of different organic reactions.16 As a continu-
ation of our research devoted to the development of new
methods for the preparation of heterocycles in environmen-
tally benign media and with iodine-catalyzed reactions,17 we
would like to synthesize these potential active compounds
in ionic liquids using various ketones, including aliphatic,
aromatic, cyclic, and heterocyclic ketones and cyclohexane-
Scheme 1. Reaction of 1 and Ketones in Ionic Liquid
Table 1. Synthetic Results of 3aa under Different Reaction
Conditionsa
entry temp./°C
ionic liquidb
I2 (mol %) time/h yield (%)c
1
2
3
4
5
6
7
8
9
50
rt
[BMIm][BF4]
[BMIm][BF4]
[BMIm][BF4]
[BMIm][BF4]
[BMIm][BF4]
[BMIm][BF4]
[EMIm]Br
[PMIm]Br
[BMIm]Br
[EMIm][BF4]
[PMIm][BF4]
0
5
5
5
5
5
5
5
5
5
5
4
4
4
4
2
6
4
4
4
4
4
72
trace
92
87
82
92
84
80
83
90
90
50
80
50
50
50
50
50
50
50
10
11
a Reaction condition: 2 mL of solvent, 2-aminobenzamide (0.272 g, 2
mmol), acetone (0.122 g, 2.1 mmol), and iodine (0.026 g, 0.1 mmol).
b BMIm ) 1-butyl-3-methylimidazolium; EMIm ) 1-ethyl-3-methylimidazo-
lium; PMIm ) 1-methyl-3-propylimidazolium. c Isolated yields.
* To whom correspondence should be addressed. E-mail: xswang1974@
yahoo.com.
10.1021/cc900174p  2010 American Chemical Society
Published on Web 03/24/2010

418 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Table 2. Synthetic Results of 3aa-cm in Ionic Liquidsa
Wang et al.
entry
R
2
time (h)
products
yields (%)b
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
acetone
butan-2-one
pentan-2-one
3-methylbutan-2-one
hexan-2-one
hexan-3-one
4-methylpentan-2-one
acetone
acetone
acetone
acetophenone
4′-nitroacetophenone
3′-chloroacetophenone
4′-chloroacetophenone
4′-methylacetophenone
4′-fluoroacetophenone
3′-bromoacetophenone
4′-bromoacetophenone
4′-nitroacetophenone
1-(3-chlorophenyl)propan-1-one
cyclopentanone
cyclohexanone
cycloheptanone
cyclooctanone
cyclododecanone
cyclohexanone
cyclohexanone
cyclohexanone
cyclohexanone
2,3-dihydroinden-1-one
1H-inden-2(3H)-one
naphthalen-1-one
1H-inden-2(3H)-one
1H-inden-2(3H)-one
1H-inden-2(3H)-one
1H-inden-2(3H)-one
tetrahydropyran-4-one
chroman-4-one
tetrahydropyran-4-one
tetrahydropyran-4-one
tetrahydropyran-4-one
tetrahydropyran-4-one
tetrahydropyran-4-one
tetrahydropyran-4-one
tetrahydrothiopyran-4-one
thiochroman-4-one
tetrahydrothiopyran-4-one
tetrahydrothiopyran-4-one
tetrahydrothiopyran-4-one
tetrahydrothiopyran-4-one
tetrahydrothiopyran-4-one
tetrahydrothiopyran-4-one
tetrahydrothiopyran-4-one
1-benzylpiperidin-4-one
ethyl 4-oxopiperidine-1-carboxylate
t-butyl 4-oxopiperidine-1-carboxylate
t-butyl 4-oxopiperidine-1-carboxylate
t-butyl 4-oxopiperidine-1-carboxylate
t-butyl 4-oxopiperidine-1-carboxylate
t-butyl 4-oxopiperidine-1-carboxylate
t-butyl 4-oxopiperidine-1-carboxylate
t-butyl 4-oxopiperidine-1-carboxylate
ethyl 4-oxopiperidine-1-carboxylate
ethyl 4-oxopiperidine-1-carboxylate
ethyl 4-oxopiperidine-1-carboxylate
4
5
4
6
4
6
5
6
4
4
8
6
7
6
8
5
6
8
6
8
6
6
6
5
5
7
8
8
7
8
6
10
6
6
6
7
6
8
6
6
6
6
4
4
4
9
6
6
6
5
5
5
9
6
6
6
8
8
8
8
6
6
8
8
8
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
92
96
95
90
95
98
93
90
90
90
89
88
90
89
86
90
87
86
92
92
89
94
90
92
82
93
93
90
88
82
92
78
89
93
93
90
90
82
88
91
92
89
93
93
87
84
85
87
82
90
83
92
80
93
88
89
83
81
84
82
92
92
79
88
76
4-MeOC6H4(CH2)2
4-FC6H4
Ph
H
H
H
H
H
H
H
H
Ph
H
H
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
3aj
3ak
3al
3am
3an
3ao
3ap
3aq
3ar
3as
3at
3au
3av
3aw
3ax
3ay
3az
3ba
3bb
3bc
3bd
3be
3bf
3bg
3bh
3bi
H
H
4-FC6H4
4-MeC6H4
Ph
4-MeOC6H4
H
H
H
Ph
4-MeOC6H4
C6H5CH2
4-MeOC6H4CH2
H
H
Ph
4-MeC6H4
4-MeOC6H4
4-FC6H4
C6H5CH2
4-MeOC6H4CH2
H
3bj
3bk
3bl
3bm
3bn
3bo
3bp
3bq
3br
3bs
3bt
3bu
3bv
3bw
3bx
3by
3bz
3ca
3cb
3cc
3cd
3ce
3cf
H
Ph
4-MeC6H4
4-MeOC6H4
C6H5CH2
4-FC6H4
4-MeOC6H4CH2
Naphthalen-2-yl
H
H
H
4-MeOC6H4
4-MeC6H4
Ph
4-FC6H4
C6H5CH2
4-MeOC6H4CH2
4-MeOC6H4
4-MeC6H4
4-FC6H4
3cg
3ch
3ci
3cj
3ck
3cl
3cm
a Reaction condition: 2 mL of [BMIm][BF4], 1 (2 mmol), 2 (2.1 mmol), and iodine (0.1 mmol), 50 °C. b Isolated yields.
1,4-dione as reactants to react with 2-aminobenzamides to
build 2,2-disubstituted quinazolin-4-(1H)-one derivatives
catalyzed by iodine. Such variations may contribute to the
bioactivity differences and enrich the compound library for
biomedical screening.
2. Results and Discussion
Treatment of 2-aminobenzamides 1 and ketones 2 in ionic
liquid of [BMIm]BF4 in the presence of 5 mol % iodine at
50 °C resulted in the corresponding 2,2-disubstituted quinazo-
lin-4-(1H)-one derivatives3aa-cm in high yields (Scheme 1).

2,2-Disubstituted Quinazolin-4(1H)-one Derivatives
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 419
Using the conversion of 2-aminobenzamide and acetone
as a model reaction, different reaction temperatures were
tested to optimize the conditions first. A summary of the
optimization experiment is listed in Table 1. In our initial
study, the reaction of 2-aminobenzamide and acetone was
carried out in the absence of iodine at 50 °C, with moderate
yield of 3aa being obtained (72%, Table 1, entry 1).
However, the other ketones we tested, in Table 2, gave poor
yields, so a small amount of iodine (10 mol %) was added
to enhance the rate of conversion. To our delight, the yield
of 3aa increased distinctly (92%), as expected. The reaction
temperature also played an important role in this reaction. It
turned out that only trace amount of product was detected
by TLC at room temperature, (Table 1, entry 2), while the
reaction went smoothly at 50 °C to produce a high yield.
To find the optimum reaction time, the reaction was carried
out in ionic liquid [BMIm][BF4] for 2, 4, and 6 h (Table 1,
entries 5, 3, and 6, respectively), resulting in the isolation
of 3aa in 82%, 92%, and 92% yield, correspondingly. Thus,
reaction conditions of 50 °C and 4 h were identified as the
optimum. Moreover, different ionic liquids were further
studied. As shown in Table 1, different groups on the
methylimidazolium, anions were chosen as media for this
reaction, and [BMIm][BF4] appeared to be the best media
for this reaction.
Figure 1. Crystal structure of the product 3ad.
After reaction completion, monitored by TLC, the reaction
mixture was allowed to cool to room temperature. A small
amount of water was added to the mixture, and the product
was isolated by filtration. Water in the filtrate was removed
by distillation under reduced pressure, and [BMIm][BF4] in
the residue could be reused after being evaporated at 80 °C
for 4 h in vacuum. Investigations using 2-aminobenzamide
and acetone as model substrates showed with with the
successive reuse of the recycled ionic liquid of [BMIm][BF4],
even in the fourth cycle, the yield of the product 3aa is fairly
high (85%).
Figure 2. Crystal structure of the product 3aw.
First of all, these optimized conditions were applied for
the conversion of various kinds of aliphatic ketones and
2-aminobenzamides 1 into the corresponding 2,2-disubsti-
tuted quinazolin-4-(1H)-one analogues (Table 2, entries
1-10). Among these analogues, ketones containing higher
hindrance, such as 3-methylbutan-2-one and 4-methylpentan-
2-one (Table 2, entries 4 and 7), also gave satisfactory results.
Even to inactive aromatic ketones, the reactions proceeded
smoothly within a few hours and resulted in good to high
yields (Table 2, entries 11-20). Subsequently, the substrate
of chain ketones was extended to cyclic ones; for example,
cyclopentanone, cyclohexanone, 3,4-dihydronaphthalen-
1(2H)-one, 2,3-dihydroinden-1-one, and 1H-inden-2(3H)-one
were also chosen to react with 2-aminobenzamides. The
desired reactions were found to generate the interesting
spirocyclic quinazolin-4-(1H)-one derivatives in high yields
(Table 2, entries 21-36).
Figure 3. Crystal structure of the product 3bs.
4-one, chroman-4-one and thiochroman-4-one. The structures
of 3ad, 3aw, and 3bs were further confirmed by X-ray
diffraction analysis, and their crystal structures are shown
in Figures 1-3, respectively.
According to the literature,18 it is believed that iodine
catalyzes the reaction as a mild Lewis acid. The proposed
mechanism is shown in Scheme 2. The Schiff base is formed
by the reaction of 2-aminobenzamide and ketone first; then
the intramolecular amino group immediately attacks iodine-
activated Schiff base to form final quinazolin-4-(1H)-one
derivatives.
In our continued study, it was also found that spiro-
heterocyclic quinazolin-4-(1H)-one derivatives were obtained
easily in high yields (Table 2, entries 37-65) under the same
reaction conditions, when the cyclic ketones were replaced
by heterocyclic ketones. These heterocyclic ketones included
tetrahydropyran-4-one, tetrahydrothiopyran-4-one, piperidin-
To obtain dispirocyclic compounds containing quinazolin-
4-(1H)-one derivatives, the cyclohexane-1,4-dione was used
to react with two molecules of 2-aminobenzamides (Scheme
3), with 1′′,3′′-dihydrospiro[1′,3′-dihydrospiro[cyclo hexane-
1,2′-quinazolin]-4′-one-4,2′′-quinazolin]-4′′-one derivatives

420 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Wang et al.
Scheme 2. Possible Mechanism for the Formation of
Products 3
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Table 3. Synthetic Results of 4aa-ah in Ionic Liquidsa
entry
R
products
time (h)
yields (%)b
1
2
3
4
5
6
7
8
H
4aa
4ab
4ac
4ad
4ae
4af
4
4
6
5
5
5
8
8
96
95
90
93
96
96
87
84
C6H5CH2
Ph
4-MeOC6H4CH2
4-MeOC6H4(CH2)2
C6H5(CH2)2
4-MeC6H4
4-FC6H4
4ag
4ah
a Reaction condition:
2
mL of [BMIm][BF4],
1
(2 mmol),
cyclohexane-1,4-dione (1.05 mmol), and iodine (0.05 mmol), 50 °C.
b Isolated yields.
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were characterized by 1H NMR, 13C NMR, IR, and HRMS.
3. Conclusion
In summary, a mild, facile and environmentally benign
method is developed for the combinatorial synthesis of
quinazolin-4-(1H)-one derivatives in high yields catalyzed
by iodine in ionic liquids. The advantages of this procedure
include its mild reaction conditions, high yields, one-pot
method, operational simplicity, and environmental benignity.
Meanwhile, this method provides new compounds containing
quinazolinone moiety for biomedical screening.
Acknowledgment. We are grateful to the National Natural
Science foundation of China (20802061), the Natural Science
foundation(08KJD150019),andQingLanProject(08QLT001)
of Jiangsu Education Committee for financial support.
Supporting Information Available. Crystallographic data
for the structures of 3ad, 3aw, and 3bs reported in this paper
have been deposited at the Cambridge Crystallographic Data
Centre as supplementary publications CCDC-758992, CCDC-
758993, and CCDC-758994, respectively. Copies of available
material can be obtained, free of charge, on application to the
Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K.
(fax: +44-(0) 1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
Representative experimental procedures and spectral data of
compounds 3aa-cm and 4aa-ah. This material is available
free of charge via the Internet at http://pubs.acs.org.

2,2-Disubstituted Quinazolin-4(1H)-one Derivatives
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 421
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